Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors

ABSTRACT

This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating disorders mediated by cyclooxygenase-2 or 5-lipoxygenase, such as inflammation.

FIELD OF THE INVENTION

[0001] This invention is in the field of antiinflammatory pharmaceuticalagents and specifically relates to compounds, compositions and methodsfor treating disorders mediated by cyclooxygenase-2 or 5-lipoxygenase,such as inflammation and allergic conditions such as asthma.

BACKGROUND OF THE INVENTION

[0002] Prostaglandins play a major role in the inflammation process, andthe inhibition of prostaglandin production, especially production ofPGG₂, PGH₂ and PGE₂, has been a common target of antiinflammatory drugdiscovery. However, common non-steroidal antiinflammatory drugs (NSAIDs)that are active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process are also active in affectingother prostaglandin-regulated processes not associated with theinflammation process. Thus, use of high doses of most common NSAIDs canproduce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

[0003] Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway including the enzyme cylooxygenase (COX). Therecent discovery of an inducible enzyme associated with inflammation(named “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H synthase II”)provides a viable target of inhibition which more effectively reducesinflammation and produces fewer and less drastic side effects.

[0004] In another portion of the arachnidonic acid pathway,physiologically active leukotrienes, such, as leukotriene B₄ (LTB₄),leukotriene C₄ (LTC₄) and leukotriene D₄ (LTD₄) and other metabolites,are produced by the 5-lipoxygenase-mediated (5-LO) oxidation ofarachidonic acid. These leukotrienes have been implicated in variousinflammation-related disorders and allergic diseases, and thus compoundswhich inhibit 5-lipoxygenase are useful in the treatment of diseasestates in which leukotrienes play an important role.

[0005] It is believed that selective dual inhibitors of bothcyclooxygenase-2 and 5-lipoxygenase, which affect the two enzymes at lowconcentrations, will more completely and permanently affect the damagecaused by the various diseases and disorders mediated bycyclooxygenase-2 and 5-lipoxygenase but without the gastrointestinalside effects associated with traditional NSAIDs.

[0006] The references below that disclose antiinflammatory activity,show continuing efforts to find a safe and effective antiinflammatoryagent. The novel compounds disclosed herein are such safe and alsoeffective antiinflammatory agents furthering such efforts. Theinvention's compounds are found to show usefulness in vivo asantiinflammatory agents with minimal side effects. The compoundsdisclosed herein preferably selectively inhibit cyclooxygenase-2 overcyclooxygenase-1.

[0007] Compounds which selectively inhabit cyclooxygenase-2 have beendescribed in U.S. Pat. Nos. 5,330,738, 5,344,991, 5,393,790 and WOdocuments WO94/15932, WO94/27980, WO95/00501, WO94/13635, WO94/20480,and WO94/26731.

[0008] Compounds which inhibit 5-lipoxygenase have been described inU.S. Pat. Nos. 5,364,877, 5,302,603, 5,234,950, 5,098,932 and 5,354,865,among others.

[0009] Compounds which inhibit cyclooxygenase and 5-lipoxygenase havebeen described in U.S. Pat. Nos. 5,298,521, 5,242,940, 5,234,939, and5,356,898, among others. However, these previous mixed inhibitors do notselectively inhibit cyclooxygenase-2 and therefore still cause thegastrointestinal side effects which substantially reduce their usage andeffectiveness.

[0010] The invention's compounds are found to show usefulness in vivo asdual inhibitors of cyclooxysenase-2 and 5-lipoxygenase with minimal sideeffects.

DESCRIPTION OF THE INVENTION

[0011] A class of compounds useful in treating cyclooxygenase-2 and5-lipoxygenase-mediated disorders is defined by Formula I:

[0012] wherein A is a 5- or 6-member ring substituent selected frompartially unsaturated or unsaturated hecerocyclo and carbocyclic rings,wherein A is optionally substituted with a radical selected from acyl,halo, alkyl, haloalkyl, cyano, nitro, carboxyl, alkoxy, oxo,aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, andhydroxyalkyl;

[0013] wherein Y is a radical selected from oxy, thio, sulfinyl,sulfonyl, alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, alkylcarbonyl,cycloalkyl, aryl, haloalkyl, hydroxyalkyl, hydroxyalkyloxy,hydroxyalkyloxyalkyl, hydroxyalkylthio, hydroxyalkylthioalkyl-,oximinoalkoxy, oximinoalkoxyalkyl, (alkyl)oximinoalkoxy,(alkyl)oximinoalkoxyallkyl, oximinoalkylthio, oximinoalkylthioalkyl,(alkyl)oximinoalkylthio, (alkyl)oximinoalkylthioalkyl, carbonylalkyloxy,carbonylalkyloxyalkyl, carbonylalkylthio, carbonylalkylthioalkyl,heterocyclo, cycloalkenyl, aralkyl, heterocycloalkyl, acyl,alkylthioalkyl, alkyloxyalkyl, alkenylthio, alkynylthio, alkenyloxy,alkynyloxy, alkenylthioalkyl, alkynylthioalkyl, alkenyloxyalkyl,alkynloxyalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,alkylarylalkynyloxy, alkylarylalkenyloxy, alkylarylalkynylthio,alkylarylalkenylthio, haloalkylcarbonyl, alkoxyalkyl,alkylaminocarbonylalkyl, heteroaralkoxyalkyl, heteroaryloxyalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, heteroaralkoxy,heteroaralkylthio, heteroaryloxy, heteroarylthio, arylthioalkyl,aryloxyalkyl, haloaryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonylcyanoalkenyl,aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl,N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloaminocarbonyl,carboxyalkylaminocarbonyl, alkylcarbonylalkyl,aralkoxycarbonylalkylaminocarbonyl, haloaralkyl, carboxyhaloalkyl,alkoxycarbonylhaloalkyl, aminocarbonylhaloalkyl,alkylaminocarbonylhaloalkyl, N-alkylamino, N,N-dialkylamino,N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,N-alkyl-N-arylamino, aminoalkyl, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aminoalkyoxy,aminoalkoxyalkyl, aminoalkylthio, aminoalkylthioalkyl, cycloalkyloxy,cycloalkylalkyloxy, cycloalkylthio, cycloalkylalkylthio, aryloxy,aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl,N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl,

[0014] wherein Ar is selected from aryl and heteroaryl, wherein Ar isoptionally substituted with one or two substituents selected from halo,hydroxyl, mercapto, amino, nitro, cyano, carbamoyl, alkyl, alkenyloxy,alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,dialkylamino, haloalkyl, alkoxycarbonyl, N-alkylcarbamoyl,N,N-dialkylcarbamoyl, alkanoylamino, cyanoalkoxy, carbamoylalkoxy,alkoxycarbonylalkoxy and

[0015] wherein R¹ is one or more substituents selected from heterocyclo,cycloalkyl, cycloalkenyl and aryl, wherein R¹ is optionally substitutedat a substitutable position with one or more radicals selected fromalkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;

[0016] wherein R² is selected from alkyl and amino;

[0017] wherein R³ and R⁴ together form a group of the formula -B-X-B¹which together with the carbon atom to which B and B¹ are attached,defines a ring having 6 ring atoms, wherein B and B¹, which may be thesame or different, each is alkylene and X is oxy, and which ring maybear one, two or three substituents, which may be the same or different,selected from hydroxyl, alkyl, alkoxy, alkenyloxy and alkynyloxy;

[0018] wherein R⁵ is selected from hydroxyl, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, carboxyl, aminocarbonyl, alkylaminocarbonyl,alkoxycarbonyl, acyl, and cyano;

[0019] wherein R⁶ is selected from hydrido, alkyl, aryl and aralkyl;

[0020] wherein R⁷ is selected from alkyl, alkoxy, alkenyl and alkynyl;

[0021] wherein R⁸ is oximino optionally substituted with alkyl; and

[0022] wherein n is 0 or 1;

[0023] provided Ar is substituted with

[0024] when A is oxazolyl;

[0025] or a pharmaceutically-acceptable salt thereof.

[0026] Compounds of Formula I would be useful for, but not limited to,the treatment of inflammation in a subject, and for treatment of otherinflammation-associated disorders, such as, as an analgesic in thetreatment of pain and headaches, or as an antipyretic for the treatmentof fever. For example, compounds of the invention would be useful totreat arthritis, including but not limited to rheumatoid arthritis,spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis Such compounds of the inventionwould be useful in the treatment of asthma, bronchitis, menstrualcramps, tendinitis, bursitis, skin-related conditions such as psoriasis,eczema, burns and dermatitis, and from post-operative inflammationincluding from ophthalmic surgery such as cataract surgery andrefractive surgery. Compounds of the invention also would be useful totreat gastrointestinal conditions such as inflammatory bowel disease,Crohn's disease, gastritis, irritable bowel syndrome and ulcerativecolitis, and for the prevention or treatment of cancer, such ascolorectal cancer. Compounds of the invention would be useful intreating inflammation in sucn diseases as vascular diseases, migraineheadaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin'sdisease, sclerodoma, rheumatic fever, type I diabetes, neuromuscularjunction disease including myasthenia graves, white matter diseaseincluding multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet'ssyndrome, polymyositis, gingivitis, nephritis, hypersensitivity,swelling occurring after injury, myocardial ischemia, and the like. Thecompounds would also be useful in the treatment of ophthalmic diseases,such as retinitis, retinopathies, uveitis, ocular photophobia, and ofacute injury to the eye tissue. The compounds would also be useful inthe treatment of pulmonary inflammation, such as that associated withviral infections and cystic fibrosis. The compounds would also be usefulfor the treatment or certain central nervous system disorders such ascortical dementias including Alzheimer's disease. The compounds of theinvention are useful as anti-inflammatory agents, such as for thetreatment of arthritis, with the additional benefit of havingsignificantly less harmful side effects. These compounds would also beuseful in the treatment of allergic rhinitis, respiratory distresssyndrome, endotoxin shock syndrome, atherosclerosis and central nervoussystem damage resulting from stroke, ischemia and trauma. The compoundswould also be useful in the treatment of pain, but not limited topostoperative pain, dental pain, muscular pain, and pain resulting fromcancer.

[0027] Besides being useful for human treatment, these compounds arealso useful for treatment of mammals, including horses, dogs, cats,rats, mice, sheep, pigs, etc.

[0028] The present compounds may also be used in co-therapies, partiallyor completely, in place of other conventional antiinflammatories, suchas together with steroids, NSAIDs, LTB₄ antagonists and LTA₄ hydrolaseinhibitors.

[0029] Suitable LTB₄ inhibitors include, among others, ebselen, BayerBay-x-1005, Ciba Geigy compound CGS-25019C, Leo Dermark compoundETH-615, Lilly compound LY-293111, Ono compound ONO-4057, Terumocompound TMK-688, Lilly compounds LY-213024, 264086 and 292728, Onocompound ONO-LB457, Searle compound SC-53228, calcitrol, Lilly compoundsLY-210073, LY223982, LY233469, and LY255283, ONO compound ONO-LB-448,Searle compounds SC-41930, SC-50605 and SC-51146, and SK&F compoundSKF-104493. Preferably, the LTB₄ inhibitors are selected from ebselen,Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compoundETH-615, Lilly compound LY-293111, Ono compound ONO-4057, and Terumocompound TMK-688.

[0030] Suitable 5-LO inhibitors include, among others, masoprocol,tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastinehydrochloride, enazadrem phosphate, and bunaprolast.

[0031] The present invention preferably includes compounds whichselectively inhibit cyclooxygenase-2 over cyclooxygenase-1 as well asinhibit the 5-lipoxygenase enzyme. Preferably, the compounds have acyclooxygenase-2 IC₅₀ of less than about 0.5 μM, and also have aselectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1inhibition of at least 50, and more oreferably of at least 100, andinhibit 5-lipooxygenase at less than about 10 μM. Even more preferably,the compounds have a cyclooxygenase-1 IC₅₀ of greater than about 1 μM,and more preferably of greater than 20 μM and have a 5-lipoxygenase IC₅₀of less than about 1 μM. Such preferred selectivity may indicate anability to reduce the incidence of common NSAID-induced side effects.

[0032] A preferred class of compounds consists of those compounds ofFormula I wherein A is a radical selected from thienyl, oxazolyl, furyl,pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, triazolyl, isoxazolyl,pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is optionallysubstituted with a radical selected from acyl, halo, lower alkyl, lowerhaloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl,lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lowerhydroxyalkyl; wherein Y is a radical selected from oxy, thio, sulfinyl,sulfonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy,lower hydroxyalkyl, lower hydroxyalkyloxy, lower hydroxyalkyloxyalkyl,lower oximinoalkoxy, lower oximinoalkoxyalkyl, lower(alkyl)oximinoalkoxy, lower (alkyl)oximinoalkoxyalkyl, lowercarbonylalkyloxy, lower carbonylalkyloxyalkyl, lower hydroxyalkylthio,lower hydroxyalkylthioalkyl, lower oximinoalkylthio, loweroximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower(alkyl)oximinoalkylthioalkyl, lower carbonylalkylthio, lowercarbonylalkylthioalkyl, lower alkylthio, lower alkylcarbonyl, lowercycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, lowercycloalkenyl, lower aralkyl, lower heterocycloalkyl, acyl, loweralkylthioalkyl, lower alkyloxyalkyl, lower alkenylthio, loweralkynylthio, lower alkenyloxy, lower alkynyloxy, lower alkenylthioalkyl,lower alkynylthioalkyl, lower alkenyloxyalkyl, lower alkynyloxyalkyl,phenylcarbonyl, lower aralkylcarbonyl, lower aralkenyl, loweralkylarylalkynyloxy, lower alkylarylalkenyloxy, loweralkylarylalkynylthio, lower alkylarylalkenylthio, lowerhaloalkylcarbonyl, lower alkylaminocarbonylalkyl, lowerheteroaralkoxyalkyl, lower heteroaryloxyalkyl, lowerheteroarylthioalkyl, lower heteroaralkylthioalkyl, lower heteroaralkoxy,lower heteroaralklthio, lower heteroaryloxy, lower heteroarylthio, lowerarylthioalkyl, lower aryloxyalkyl, lower aralkylthioalkyl, loweraralkoxyalkyl, lower alkoxyaralkoxalkyl, lower alkoxycarbonylalkyl,lower alkoxycarbonylcyanoalkenyl, lower aminocarbonylalkyl, lowerN-alkylaminocarbonyl, N-phenylaminocarbonyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lowercycloalkylaminocarbonyl, lower heterocycloaminocarbonyl, lowercarboxyalkylaminocarbonyl, lower alkylcarbonylalkyl, loweraralkoxycarbonylalkylaminocarbonyl, lower haloaralkyl, lowercarboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, loweraminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lowerN-alkylamino, lower N,N-dialkylamino, N-phenylamino, lowerN-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino,lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl,lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lowerN-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, loweraminoalkoxy, lower aminoalkoxyalkyl, lower aminoalkylthio, loweraminoalkylthioalkyl, lower cycloalkyloxy, lower cycloalkylalkyloxy,lower cycloalkylthio, lower cycloalkylalkylthio, phenyloxy, loweraralkoxy, phenylthio, lower aralkylthio, lower alkylsulfinyl, loweralkylsulfonyl, aminosulfonyl, lower N-alkylaminosulfonyl, lowerN-arylaminosulfonyl, lower arylsulfonyl, lower N,N-dialkylaminosulfonyl,lower N-alkyl-N-aylaminosulfonyl,

[0033] wherein Ar is selected from aryl selected from phenyl, blphenyland naphthyl, and 5- and 6-membered heteroaryl, wherein Ar is optionallysubstituted with one or two substituents selected from halo, hydroxyl,mercapto, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy,lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,lower alkylamino, lower dialkylamino, lower haloalkyl, loweralkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl,lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, loweralkoxycarbonylalkoxy and

[0034] wherein R¹ is at least one substituent selected from 5- and6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and arylselected from phenyl, biphenyl and naphthyl, where R¹ is optionallysubstituted at a substitutable position with one or more radicalsselected from lower alkyl, lower haloalkyl, cyano, carboxyl, loweralkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino,lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, loweralkylsulfinyl, halo, lower alkoxy and lower alkylthio; wherein R² isselected from lower alkyl and amino; wherein R³ and R⁴ together form agroup of the formula —B—X—B¹ which togethner with the carbon atom towhich B and B¹ are attached, defines a ring having 6 ring atoms, whereinB and B¹, which may be the same or different, each is alkylene and X isoxy, and which ring may bear one, two or three substituents, whicn maybe the same or different, selected from hydroxyl, lower alkyl, loweralkoxy, lower alkenyloxy and lower alkynloxy; wherein R⁵ is selectedfrom hydroxyl, lower alkoxy, lower alkylcarbonyloxy, phenylcarbonyloxy,carboxyl, aminocarbonyl, lower alkylaminocarbonyl, lower alkoxycarbonyl,lower acyl, and cyano; wherein R⁶ is selected from hydrido, lower alkyl,phenyl and lower aralkyl; wherein R⁷ is seleced from lower alkyl, loweralkoxy, lower alkenyl and lower alkynyl; wherein R⁸ is oximinooptionally substituted with alkyl; and wherein n is 0 or 1; or apharmaceutically-acceptable salt thereof.

[0035] A more preferred class of compounds consists of those compoundsof Formula I wnerein A is a radical selected from thienyl, oxazolyl,furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, triazolyl,isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl, werein A isoptionally substituted with a radical selected from acyl, halo, loweralkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy,aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lowercyanoalkyl, and lower hydroxyalkyl; wherein Y is a radical selected fromoxy, thio, sulfinyl, sulfonyl, lower alryl, lower alkenyl, loweralkynyl, lower alkyloxy, lower hydroxyalkyl, lower hydroxyalkyloxy,lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, loweroximinoalkoxyalkyl, lower (alkyl)oximinoalkoxy, lower(alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, lowercarbonylalkyloxyalkyl, lower hydroxyalkylthio, lowerhydroxyalkylthioalkyl, lower oximinoalkalkylthio, loweroximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower(alkyl)oximinoalkylthioalkyl, lower carbonylalkylthio, lowercarbonylalkylthioalkyl, lower alkylthio, lower alkylcarbonyl, lowercycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, lowercycloalkenyl, lower aralkyl, lower heterocycloalkyl, acyl, loweralkylthioalkyl, lower alkyloxyalkyl, lower alkenylthio, loweralkynylthio, lower alkenyloxy, lower alkynyloxy, lower alkenylthioalkyl,lower alkynylthioalkyl, lower alkenyloxyalkyl, lower alkynyloxyalkyl,phenylcarbonyl, lower aralkylcarbonyl, lower aralkenyl, loweralkylarylalkynyloxy, lower alkylarylalkynylthio, lowerhaloalkylcarbonyl, lower alkylaminocarbonylalkyl, lower arylthioalkyl,lower aryloxyalkyl, lower aralkylthioalkyl, lower aralkoxyalkyl, loweralkoxycarbonylalkyl, lower aminocarbonylalkyl, lowerN-alkylaminocarbonyl, N-phenylaminocarbonyl, lower alkylcarbonylalkyl,lower N-alkylamino, N-phenylamino, lower N-aralkylamino, loweraminoalkyl, lower N-alkylaminoalkyl, lower N-arylaminoalkyl, lowerN-aralkylaminoalkyl, lower aminoalkoxy, lower aminoalkoxyalkyl, loweraminoalkylthio, lower aminoalkylthioalkyl, lower cycloalkyloxy, lowercycloalkylalkyloxy, lower cycloalkylthio, lower cycloalkylalkylthio,phenyloxy, lower aralkoxy, phenylthio, lower aralkylthio, loweralkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lowerN-alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, oximino,

[0036] wherein Ar is selecaed from aryl selected from phenyl, biphenyl,naphthyl, and, 5- and 6-membered heteroaryl, wherein Ar is optionallysubstituted with one or two substituents selected from halo, hydroxyl,mercapto, amino, nitro, cyano, lower alkyl, lower alkoxy, and

[0037] wherein R¹ is at least one substituent selected from 5- and6-membered heteroaryl, and aryl selected from phenyl, biphenyl andnaphthyl, where R¹ is optionally substituted at a substitutable positionwith one or more radicals selected from lower alkyl, lower haloalkyl,cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl,lower haloalkoxy, amino, nitro, lower alkoxyalkyl, lower alkylsulfinyl,halo, lower alkoxy and lower alkylthio; wherein R² is selected fromlower alkyl and amino; wherein R³ and R⁴ together form a tetrahydropyranring and which ring may bear one, two or three substituents, which maybe the same or different, selected from hydroxyl, lower alkyl, and loweralkoxy; wherein R⁵ is selected from hydroxyl and lower alkoxy; whereinR⁶ is selected from hydrido, lower alkyl, phenyl and lower aralkyl; andwherein R⁷ is selected from lower alkyl, lower alkoxy, lower alkenyl andlower alkynyl; or a pharmaceutically-acceptable salt thereof.

[0038] An even more preferred class of compounds consists of thosecompounds of Formula I wherein A is a radical selected from thienyl,oxazolyl, furyl, pyrrolyl, thiazolyl, triazolyl, imidazolyl, isoxazolyl,pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is optionallysubstituted with a radical selected from acyl, halo, lower alkyl, lowerhaloalkyl, oxo, cyano, carboxyl, lower allkoxy, aminocarbonyl, loweralkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lowerhydroxyalkyl; wherein Y is a radical selected from oxy, thio, sulfinyl,sulfonyl, lower alkyl, lower alkynyl, lower alkenyl, aryl, lowercycloalkyl, 5- or 6-membered heterocyclo, aralkyl, lower alkyloxy,aryloxy, arylthio, 5- or 6-membered heterocyclooxy, lower aralkylthio,lower aralkyloxy, lower alkylthio, lower alkynyloxy, lower alkynylthio,lower alkynyloxyalkyl, lower alkenyloxy, lower alkenylthio, loweralenyloxyalkyl, lower alkyloxyalkyl, lower alkylthioalkyl, lowerhydroxyalkyloxy, lower alkylarylalkynyloxy, lower alkoxycarbonylalkyl,lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, loweroximinoalkoxyalkyl, lower (alkyyl)oximinoalkoxy, lower(alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, lowercarbonylalkyloxyalkyl,

[0039] wherein Ar is selected from phenyl, thienyl, oxazolyl, furyl,pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl,and pyridyl, wnerein Ar is optionally substituted with one or twosubstituents selected from halo, hydroxyl, mercapto, lower alkyl, loweralkoxy, and

[0040] wherein R¹ is at least one substituent selected from thienyl,oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl,isoxazolyl, pyrazolyl, cyclopentenyl, pyridyl, and phenyl, where R¹ isoptionally substituted at a substitutable position with one or moreradicals selected from lower alkyl, lower haloalkyl, hydroxyl, lowerhydroxyalkyl, lower haloalkoxy, nitro, lower alkoxyalkyl, halo, loweralkoxy and lower alkylthio; wherein R² is selected from lower alkyl andamino; wherein R³ and R⁴ together form a tetrahydropyran ring, and whichring may bear one, two or three substituents, which may be the same ordifferent, selected from hydroxyl, lower alkyl, and lower alkoxy;wherein R⁵ is selected from hydroxyl and lower alkoxy; wherein R⁶ isselected from hydrido, and lower alkyl; and wherein R⁷ is selected fromlower alkyl and lower alkoxy; or a pharmaceutically-acceptable saltthereof.

[0041] A class of compouncs of particular interest consists of thosecompounds of Formula I wherein A is a radial selected from thienyl,oxazolyl, furyl, pyrrolyl, triazolyl, thiazolyl, imidazolyl, isoxazolyl,pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is optionallysubstituted with a radical selected from acyl, fluoro, chloro, bromo,methyl, trifluoromethyl, oxo, cyano, carboxyl, methoxy, aminocarbonyl,methoxycarbonyl, ethoxycarbonyl, acetyl, carboxypropyl, andhydroxymethyl; wherein Y is a radical selected from oxy, ethyl, propyl,isopropyl, butyl, 1-propynyl, 2-propynyl, methyloxy, ethyloxy,propyloxy, methylthio, (Z)-1-propenyloxy, (E)-2-propenyloxy,(Z)-2-propenyloxy, (E)-1-prooenyloxy, (Z)-1-propenyloxymethyl,(E)-2-propenyloxmethyl, (Z)-2-propenyloxymethyl,(E)-1-propenyloxymethyl, 1-propynyloxy, 2-propynyloxy, 1-propynylthio,2-propynylthio, hydroxymethyloxy, 1-hydroxyethyloxy, 2-hydroxyproploxy,hydroxymethyloxymethyl, 1-hydroxyethyloxymethyl,2-hydroxypropyloxymethyl, methyloxymethyl, ethyloxymethyl,propyloxymethyl, 1-propynyloxymethyl, oximinomethyloxy,oximinomethyloxymethyl, (methyl)oximinomethyloxy,(methyl)oximinomethyloxymethyl, triazolylmethyloxy,triazolylmethyloxymethyl, 1-(methoxycarbonyl)ethyl, methylthiomethyl,ethylthiomethyl, methylphenylpropynyloxy,N-ethyl-N-methylaminocarbonylmethyloxy, N-ethyl-N-methylaminoethyloxy,carbonylmethyloxy, carborylbutyloxy, and carbonylmethyloxymethyl;wherein Ar is selected from thienyl, pyridyl, thiazolyl, and phenyl,where Ar is optionally substituted with one or two substituents selectedfrom fluoro, chloro, bromo, hydroxyl, mercapto, methyl, methoxy, and

[0042] wherein R¹ is selected from thienyl, oxazolyl, furyl, pyrrolyl,thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, and phenyl, whereR¹ is optionally substituted at a substitutable position with one ormore radicals selected from methyl, trifluoromethyl, hydroxyl,hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chloro,bromo, methoxy and methylthio; wherein R² is methyl or amino; wherein R³and R⁴ together from a tetrahydropyran ring, and which ring may bearone, two or three substituents, which may be the same or different,selected from hydroxyl, methyl, and methoxy; and wherein R⁵ is selectedfrom hdroxyl and methoxy; or a pharmaceutically-acceptable salt thereof.

[0043] Within Formula I there is a subclass cf compounds of highinterest represented by Formula II:

[0044] wherein A is a ring substituent selected from thienyl, oxazolyl,furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, triazolyl,isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A isoptionally substituted with a radical selected from acyl, halo,hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl,lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl,lower cyanoalkyl, and lower hydroxyalkyl;

[0045] wherein Y is a radical selected from oxy, thio, sulfinyl,sulfonyl, lower alkyl, lower alkynyl, lower alkenyl, lower hydroxyakyl,aryl, lower cycloalkyl, 5- or 6-membered heterocyclo, aralkyl, loweralkyloxy, aryloxy, arylthio, lower cycloalkyloxy, 5- or 6-memberedheterocyclooxy, lower aralkylthio, lower aralkyloxy, lower alkylthio,lower alkynyloxy, lower alkynylthio, lower alkynyloxyalkyl, loweralkenyloxy, lower alkenylthio, lower alkenyloxyalkyl, loweralkyloxyalkyl, lower alkylthioalkyl, lower hydroxyalkylthio, lowerhydroxyalkylthioalkyl, lower oximinoalkylthio, loweroximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower(alkyl)oximinoalkylthioalkyl, lower alkylarylalkynyloxy, lowerdialkylaminoalkyloxy, lower dialkylaminocarbonylalkyloxy, loweralkoxycarbonylalkyl, lower carbonylalkylthio, lowercarbonylalkylthioalkyl, lower hydroxyalkyloxy, lowerhydroxyalkyloxyalkyl, lower oximinoalkoxy, lower oximinoalkoxyalkyl,lower (alkyl)oximinoalkoxy, lower (alkyl)oximinoalkoxyalkyl, lowercarbonylalkyloxy, and lower carbonylalkyloxyalkyl;

[0046] wherein R¹ is a substituent selected from 5- and 6-memberheterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected fromphenyl, biphenyl and naphthyl, whereinr R¹ is optionally substituted ata substitutable position with one or more radicals selected from loweralkyl, lower haloalkyl, cyano, carboxyl, lower alkoxcycarbonyl,hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxyand lower alkylthio;

[0047] wherein R² is selecced from lower alkyl and amino;

[0048] wherein R⁹ is one or two substituents selected from halo,hydroxyl, amino, nitro, cyano, carbamoyl, alkyl, alkenyloxy, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino,haloalkyl, alkoxycarbonyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl,alkanoylamino, cyanoalkoxy, carbamoylalkoxy, and alkoxycarbonylalkoxy;and

[0049] wherenin R¹⁰ is selected from hydrido, alkyl, alkenyl, alkynyl,cyanoalkyl, alkanoyl, and benzoyl optionally substituted with asubstituent selected from halo, alkyl, and alkoxy;

[0050] or a pharmaceutically-acceptable salt thereof.

[0051] A preferred class of compounds consists of those compounds ofFormula II wherein A is a ring substituent selected from thienyl,oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, triazoylyl,isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A isoptionlly substituted with a radical selecced from acyl, halo, hydroxyl,lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy,aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lowercyanoalkyl, and lower hydroxyalkyl, wherein Y is a radical selected fromoxy, lower alkyl, lower alkynyl, 5- or 6-membered heterocyclo, lowerheterocyloalkyloxyalkyl, lower hydroxyalkyl, lower alkyloxy, loweralkylthio, lower alkyloxyalkyl, lower alkenyloxy, lower alkenyloxyalkyl,lower alkynyloxy, lower alkynylthio, lower alkynyloxyalkyl, loweralkylthioalkyl, lower hydroxyalkylthio, lower hydroxyalkylthioalkyl,lower oximinoalkylthio, lower oximinoalkylthioalkyl, lower(alkyl)oximinoalkylthio, lower (alkyl)oximinoalkylthioalkyl, lowercarbonylalkylthio, lower carbonylalkylthioalkyl, loweralkylarylalkynyloxy, lower dialkylaminoalkyloxy, lowerdialkylaminocarbonylalkyloxy, lower alkoxycarbonylalkyl, lowerhydroxyalkyloxy, lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, loweroximinoalkoxyalkyl, lower (alkyl)oximinoalkoxy, lower(alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, and lowercarbonylalkyloxyalkyl; wherein R¹ is phenyl optionally substituted at asubstitutable position with one or more radicals selected from loweralkyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, halo, and loweralkoxy; wherein R² is selected from lower alkyl and amino; wherein R⁹ isone or two substituents selected from halo, hydroxyl, amino, loweralkyl, lower alkoxy; and wherein R¹⁰ is selected from hydrido, and loweralkyl; or a pharmaceutically-acceptable salt thereof.

[0052] A class of compounds of particular interest consists of thosecompounds of Formula II wherein A is a radical selected from thienyl,oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl,cyclopentenyl, phenyl, and pyridyl; wherein A is optionally substitutedwith a radical selected from formyl, fluoro, chloro, bromo, hydroxyl,methlyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, oxo, cyano, nitro, carboxyl, methoxy, ethoxy, propoxy,n-butoxy, pentoxy, hexyloxy, methylenedioxy, aminocarbonyl,methoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl,cyanomethyl, and hydroxymethyl; wherein Y is a radical selected fromoxy, ethyl, propyl, isopropyl, butyl, 1-propynyl, 2-propynyl, methyloxy,ethyloxy, propyloxy, methylthio, (Z)-1-propenyloxy, (E)-2-propenyloxy,(Z)-2-proenyloxy, (E)-1-propenyloxy, (Z)-1-properyloxymethyl,(E)-2-propenyloxymethyl, (Z)-2-propenyloxymethyl,(E)-1-propenyloxymethyl, 1-propynyloxy, 2-propynyloxy, 1-propynylthio,2-propynylthio, hydroxymethyl, hydroxyethyl, hydroxypropyl,hyrdroxymethyloxy, 1-hydroxyethyloxy, 2-hydroxypropyloxy,hydroxymethyloxymethyl, 1-hydroxyethyloxymethyl,2-hydroxypropyloxymethyl, methyloxymethyl, ethyloxymethyl,propyloxymethyl, 1-propynyloxymethyl, hydroxymethlylthio,1-hydroxyethylthio, 2-hydroxypropylthio, hydroxymethylthiomethyl,1-hydroxyethylthiomethyl, 2-hydroxypropylthiomethyl, oximinomethylthio,oximinomethylthiomethyl, (metnhl)oximinomethylthio,(methyl)oximinomethylthiomethyl, triazolylmethyloxy,triazolylmethyloxymethyl, carbonylmethylthio, carbonylbutylthio,carbonylmethylthiomethyl, oximinomethyloxy, oximinomethyloxymethyl,(methyl)oximinomethyloxy, methylthiomethyl,(methyl)oximinomethyloxymethyl, ethylthiomethyl,1-(methoxycarbonyl)ethyl, methylphenylpropynyloxy,N-ethyl-N-methylaminocarbonylmethyloxy, N-ethyl-N-methylaminoethyloxy,triazolyl, carbonylmethyloxy, carbonylbutyloxy, andcarbonylmethyloxymethyl; wherein R¹ is phenyl optionally substituted ata substitutable position with one or more radicals selected from methyl,ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, fluoro,dichloropropyl, hydroxyl, hydroxylmethyl, chloro, bromo, methoxy,ethoxy, propoxy, n-butoxy, pentoxy, and hexyloxy; wherein R² is selectedfrom methyl and amino; wherein R⁹ is one or two substituents selectedfrom fluoro, chloro, bromo, hydroxyl, amino, methyl, ethyl, isopropyl,butyl, tezt-butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, propoxy,n-butoxy, pentoxy, and hexyloxy; and wherein R¹⁰ is selected fromhydrido, and methyl; or a pharmaceutically-acceptable salt thereof.

[0053] A class of compounds of particular interest consists of thosecompounds of Formula I

[0054]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-(3-fluoro-4-methoxyphenyl)oxazol-5-yl]benzenesulfonamide;

[0055]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-(3,4-dichlorophenyl)oxazol-5-yl]benzenesulfonamide;

[0056]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-(3-fluorophenyl)oxazol-5-yl]benzenesulfonamide;

[0057]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-(4-methylphenyl)oxazol-5-yl]benzenesulfonamide;

[0058]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4methoxy-2-methylpyran-4-yl)phenoxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0059]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-2,6-dimethyl-4-methoxypyran-4-yl)phenoxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0060][5-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-4-phenyloxazole;

[0061]4-[-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-5-(3-fluoro-4-methoxyphenyl)oxazol-4-yl]benzenesulfonamide;

[0062]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methy]-5-(3,4-dichlorophenyl)oxazol-4-yl]benzenesulfonamide;

[0063]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-5-(3,4-dichlorophenyl)oxazol-4-yl]benzenesulfonamine;

[0064]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-5-(4-methylphenyl)oxazol-4-yl]benzenesulfonamide;

[0065]4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2-methyplyran-4-yl)phenoxy]methyl]-5-phenyloxazol-4-yl]benzenesulfonamide;

[0066]4-[2-[[3-fluoro-5-(3,4,5,6-terahydro-2,6-dimethyl-4-methoxypyran-4-yl)phenoxy]methyl]-5-phenyloxazol-4-yl]benzenesulfonamide;

[0067][4-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-5-phenyloxazole;

[0068]4-[2-[[4-(3,4,5,6-tetrahydro-4-methoxy-2-methylpyran-4-yl)thien-2-yl]thiomethyl]-5-phenyloxazol-4-yl]benzenesulfonamide;

[0069]4-[2-[[4-(3,4,5,6-tetrahydro-4-methoxy-2-methylpyran-4-yl)thien-2-yl]thio]-5-phenyloxaziol-4-yl)]benzenesulfonamide;

[0070]4-[2-[[4-(3,4,5,6-tetrahydaro-2,6-dimethyl-4-methoxyyran-4-yl)thien-2-yl]thiomethyl]-5-phenyloxazol-4-yl]benzenesulfonamide;

[0071]4-[2-[[4-(3,4,5,6-terahydro-2,6-dimethyl-4-methoxypyran-4-yl)thien-2-yl]thio]-5-phenyloxazol-4-yl]benzenesulfonamide;

[0072]4-[2-[[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0073] methyl5-[4-(aminosulfonyl)phenyl]-α-[[3-(tetrahydro-4-methoxypyran-4-yl)phenyl]methyl]-4-phenyloxazole-2-acetate;

[0074]N-[2-[5-[4-(aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamide;

[0075]N-[2-[4-[4-(aminosulfonyl)phenyl]-5-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamide;

[0076]4-[2-[[2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]ethyl]-N-methylaminoethyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0077]4-[2-[[2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]ethyl]-N-methylaminoethyl]-5-phenyloxazol-4-yl]benzenesulfonamide;

[0078]4-[2-[[4-[3-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]-1-propynyl]phenyl]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0079]4-[2-[[4-[3-[3-fluoro-5-(tetrahydro-4-hydroxypyran-4-yl)phenoxy]-1-propynyl]-phenyl]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0080]4-[2-[[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoy]methyl]-4-(4-fluoropenyl)oxazol-5-yl]benzenesulfonamide;

[0081]4-[2-[4-[[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]phenylmethyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0082]4-[5-[[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-3-phenylisoxazol-4-yl]benzenesulfonamide;

[0083]4-[2-[[[3-(tetrahydro-4-methoxypyran-4-yl)phenylmethyl]oxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0084]4-[2-[[[3-(tetrahydro-4-methoypyran-4-yl)phenylmethyl]thio]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0085]4-[2-[[3-(tetrahyro-4-methoxypyran-4-yl)phenylmethyl]thio]ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0086]4-[2-[3-(tetrahydro-4-methoxypyran-4-yl)phenyl]-methoxy]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0087]4-[2-[3-(tetrahydro-4-methoxypyran-4-yl)phenyl]methylthio]-4-phenyloxazol-5-yl]benzenesulfonamide;

[0088]N-[2-[5-[4-(aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethylamino]-2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]acetamide;

[0089] 4-[5-(4-chlorophenyl)-3-(3-methoxyphenyl)oxymethyl-1Hpyrazol-1-yl]benzenesulfonamide;

[0090] 4-[5-(4-chloropheny)-3-(3-methoxyphenyl)thiomethyl-1Hpyrazol-1-yl]benzenesulfonamide;

[0091]4-[5-phenyl-3-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-1H-pyrarzol-1-yl]benzenesulfonamide;

[0092]1-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-5-phenylpyrazol;

[0093]4-[5-phenyl-3-[[3-flouro-5-(3,4,5,6-tetrahydro-4-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-1H-pyrazol-1-yl]benzenesulfonamide;

[0094]4-[5-phenyl-3-[[3-flouro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-1H-pyrazol-1-yl]benzenesulfonamide;

[0095]4-[5-phenyl-3-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-1H-pyrazol-1-yl]benzenesulfonamnide;

[0096]4-[5-(4-chlorophenyl)-3-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pheroxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide;

[0097]4-[1-phenyl-3-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-1H-pyrazol-5-yl]benzenesulfonamide;

[0098]4-[1-phenyl-3-[[3-flouro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-1H-pyrazol-5-yl]benzenesulfonamide;

[0099]4-[1-phenyl-3-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-1H-pyrazol-5-yl]benzenesulfonamide;

[0100]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2-H-pyran-4-yl)phenoxy]acetyl]-5-thiazolyl]benzenesulfonamide;

[0101]5-phenyl-4-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]thiazole;

[0102]4-[5-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-4-thiazolyl]benzenesulfonamide;

[0103]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-5-thiazolyl]benzenesulfonamide;

[0104]4-[3-phenyl-5-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-4-isoxazolyl]benzenesulfonamide;

[0105]3-phenyl-4-[4-(methylsulfonyl)phenyl]-5-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]isoxazole;

[0106]4-[3-phenyl-5-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-4-isoxazolyl]benzenesulfonamide;

[0107]4-[3-phenyl-5-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-4-isoxazolyl]benzenesulfonamide;

[0108]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-1-imidazolyl]benzenesulfonamide;

[0109]5-phenyl-4-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]imidazole;

[0110]4-[5-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-4-imidazolyl]benzenesulfonamide;

[0111]4-[2-phenyl-4-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-1-imidazolyl]benzenesulfonamide;

[0112]4-[3-phenyl-4-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-2-pyridyl]benzenesulfonamide;

[0113]3-phenyl-2-[4-(methylsulfonyl)phenyl]-4-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]pyridine;

[0114]4-[2-phenyl-4-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-3-pyridyl]benzenesulfonamide;

[0115]4-[2-phenyl-4-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-3-pyridyl]benzenesulfonamide;

[0116] 4-[2-[3-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide;

[0117]4-[2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide;

[0118]4-(4-fluorophenyl)-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]-5-(4-(methylsulfonyl)phenyl)oxazole;

[0119]4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]oxazole;

[0120]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0121]4-phenyl-5-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]oxazole;

[0122]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0123]4-[4-phenyl-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0124]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0125]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)2-thienayloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0126]4-[4-(4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)-3-pyridinyloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0127]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)-3-pyridylmethoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0128]4-phenyl-2-[[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0129]4-phenyl-2-[[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0130]4-phenyl-2-[[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0131] 4-phenyl-2-[[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0132]4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0133]4-phenyl-5-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2-H-pyran-4-yl-)phenoxy]acetyl]oxazole;

[0134]4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-y1)phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0135]4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0136]4-phenyl-2-[[3-flouro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-4-pyran-4-yl)benzyloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0137]4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thienyloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0138]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0139]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0140]4-[4-phenyl-2-[[6-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0141]4-[4-phenyl-2-[[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0142]4-[4-phenyl-2-[[2-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0143] 4-[4-phenyl-2-[[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0144]4-[4-phenyl)-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2-H-pyran-4-yl)phenoxy](E-oximinomethyl)ethyl]-5-oxazolyl]benzenesulfonamide;

[0145]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy](Z-oximinomethyl)ethyl]-5-oxazolyl]benzenesulfonamide;

[0146]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-4-methoxy-2H-pyran-4-yl)phenoxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0147]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0148]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[2-3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenyl](E-oximinomethyl)ethyl-]oxazole;

[0149]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy](Z-oximinomethyl)ethyl]oxazole;

[0150]4-[4-phenyl-2-[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0151]4-[4-phenyl-2-[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0152]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0153]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0154]4-[4-phenyl-2-[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0155]4-[4-phenyl-2-[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0156]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thienyloxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0157]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thienyloxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0158]4-[4-phenyl-2-[2-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0159]4-[4-phenyl-2-[2-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0160]4-[4-phenyl-2-[2-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0161]4-[4-phenyl-2-[2-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0162]4-[4-phenyl-2-[2-[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0163]4-[4-phenyl-2-[2-[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0164]4-[4-phenyl-2-[2-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0165]4-[4-phenyl-2-[2-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0166]4-[4-phenyl-2-[2-[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0167]4-[4-phenyl-2-[2-[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0168] 4-[4-phenyl-2-[2-[3-fluoro-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy](Z-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0169] 4-[4-phenyl-2-[2-[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy](E-oximino)ethyl]-5-oxazolyl]benzenesulfonamide;

[0170] 4-[4-phenyl-b2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0171]4-phenyl-5-[4-[4-(methylsufonyl)phenyl]-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]propyn-1-yl]oxazole;

[0172]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0173]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0174]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0175]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)-thienyloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0176]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0177]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0178]4-[4-phenyl-2-[3-[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0179]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0180]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0181] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0182]4-[4-phenyl-2-[3-[3-(3,4,5,6tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0183]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]propyn-1-yl]oxazole;

[0184]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0185]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0186]4-[4-phenyl-2-[3-[3-3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0187]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thienyloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0188]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0189]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0190]4-[4-phenyl-2-[3-[6-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0191]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0192]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0193] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0194]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0195]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]propyl]oxazole;

[0196]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]propyl]-5-oxazolyl]1benzenesulfonamide;

[0197] 4-[4-phenyl-2-[3-[3-(3,4,5,6tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0198]4-[4-phenyl-2-[3-[3-flouro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0199]4-[4-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)-2-thienyloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0200]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0201]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0202]4-[4-phenyl-2-[3-[4-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]propyn]-5-oxazolyl]benzenesulfonamide;

[0203]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0204]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0205] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenyl]propyl]-5-oxazolyl]benzenesulfonamide;

[0206]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4yl)phenoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0207]4-[4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]propyl]-5-oxazole;

[0208]4-[4-phenyl-2-[3-[3-flouro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0209]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0210]4-[4-phenyl-2-[3-[3-flouro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0211]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)-2-thienyloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0212]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0213]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0214]4-[4-phenyl-2-[3-[6-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0215]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0216]4-[4-phenyl-2-[3-[2-(3,4,5,6tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0217] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]propyl]-5-oxazolyl]benzenesulfonamide;

[0218]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0219]4-[4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]ethyl]oxazole;

[0220]4-[4-phenyl-2-[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0221]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0222]4-[4-phenyl-2-[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0223]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)-5-thienyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0224]4-[4-phenyl-2-[2-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0225]4-[4-phenyl-2-[2-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0226]4-[4-phenyl-2-[2-[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0227]4-[4-phenyl-2-[2-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0228]4-[4-phenyl-2-[2-[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0229] 4-[4-phenyl-2-[2-[3-fluoro-5-(1S,5S3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0230]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-y)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0231]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[2-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]ethyl]oxazole;

[0232]4-[4-phenyl-2-[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]ethyl]-5-oxazolylbenzenesulfonamide;

[0233]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0234]4-[4-phenyl-2-[2-[3-flouro-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0235]4-[4-phenyl-2-[2-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)-5-thienyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0236]4-[4-phenyl-2-[2-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0237]4-[4-phenyl-2-[2-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0238]4-[4-phenyl-2-[2-[6-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0239]4-[4-phenyl-2-[2-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0240]4-[4-phenyl-2-[2-[2-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0241] 4-[4-phenyl-2-[2-[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0242]4-[4-phenyl-2-[1-hydroxy-2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0243]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[1-hydroxy-2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]ethyl]oxazole;

[0244]4-[4-phenyl-2-[1-hydroxy-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4yl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0245]4-[4-phenyl-2-[1-hydroxy-2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0246]4-[4-phenyl-2-[1-hydroxy-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0247]4-[4-phenyl-2-[1-hydroxy-2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiophenyl]ethyl]-5-oxazolyl]benzenesulfonamide;

[0248]4-[4-phenyl-2-[1-hydroxy-2-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0249]4-[4-phenyl-2-[1-hydroxy-2-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0250]4-[4-phenyl-2-[1-hydroxy-2-[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0251]4-[4-phenyl-2-[1-hydroxy-2-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0252]4-[4-phenyl-2-[1-hydroxy-2-[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0253] 4-[4-phenyl-2-[1-hydroxy-2-[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0254]4-[4-phenyl-2-[1-hydroxy-2-[3-(3,4,5,6-tetrahydro-4-hydroxy-2-H-pyran-4-yl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0255]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[1-hydroxy-2-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]ethyl]oxazole;

[0256]4-[4-phenyl-2-[1-hydroxy-2-[3-flouro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0257]4-[4-phenyl-2-[1-hydroxy-2-3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0258]4-[4-phenyl-2-[1-hydroxy-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0259]4-[4-phenyl-2-[1-hydroxy-2-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiophenyl]ethyl]-5-oxazolyl]benzenesulfonamide;

[0260]4-[4-phenyl-2-[1-hydroxy-2-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0261]4-[4-phenyl-2-[1-hydroxy-2-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0262]4-[4-phenyl-2-[1-hydroxy-2-[6-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0263]4-[4-phenyl-2-[1-hydroxy-2-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0264]4-[4-phenyl-2-[1-hydroxy-2-[2-(3,4,5,6-tetrahydro-4-hydroxy-2-pyran-4-yl)thiazol-4-ylmethoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0265] 4-[4-phenyl-2-[1-hydroxy-2-[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]ethyl]-5-oxazolyl]benzenesulfonamide;

[0266]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0267]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]oxazole;

[0268]4-[4-phenyl-2-[[3-flouro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0269]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0270]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0271]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiophenyl]methyl]-5-oxazolyl]benzenesulfonamide;

[0272]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0273]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0274]4-[4-phenyl-2-[[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0275]4-[4-phenyl-2-[[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0276]4-[4-phenyl-2-[[2-(3,4,56-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0277] 4-[4-phenyl-2-[[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0278]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0279]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]methyl]oxazole;

[0280]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0281]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0282]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0283]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiophenyl]methyl]-5-oxazolyl]benzenesulfonamide;

[0284]4-[4-phenyl-2[-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yloxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0285]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0286]4-[4-phenyl-2-[[6-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0287]4-[4-phenyl-2-[[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0288]4-[4-phenyl-2-[[2-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]methyl]-5-oxazolyl]benzenesulfonamide;

[0289] 4-[4-phenyl-2-[[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1-]octanyl)phenoxy]methyl]-5-oxazolyl]benzenesulfonamide;4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy](E-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0290]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy](E& Z-propen)-1-yl]oxazole;

[0291]4-[4-phenyl-2-[3-fluoro-5-(3,4,5,6,-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0292]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0293]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0294]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiophenyl](E-propen)-1-yl-5-oxazolyl]benzenesulfonamide;

[0295]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0296]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy](E-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0297]4-[4-phenyl-2-[3-[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy](Z-propen)-1-yl]-5-oxazolyl[benzenesulfonamide;

[0298]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0299]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-methoxy-2-pyran-4-yl)thiazol-4-ylmethoxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0300] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0301]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy](E-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0302]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy](E-propen)-1-yl]oxazole;

[0303]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy](Z-propen)-yl-1-5-oxazolyl]benzenesulfonamide;

[0304]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy](E-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0305]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0306]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiophenyl](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0307]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yloxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0308]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-ylmethoxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0309]4-[4-phenyl-2-[3-[6-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-2-ylmethoxy](E-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0310]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy](E-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0311]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-ylmethoxy](Z-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0312] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy](E-propen)-1-yl]-5-oxazolyl]benzenesulfonamide;

[0313]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0314]4-[4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0315]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]-1,2,3-triazol-4-methoxy-2H-pyran-4-yl)phenoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0316]4-[4-phenyl-2-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy-1,2,3-triazol]-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0317]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0318]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiophenyl]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0319]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yloxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0320]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0321]4-[4-phenyl-2-[[6-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0322]4-[4-phenyl-2-[-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)benzyloxy]-1,2,3-triazol-4-yl-methyl-5-]-5-oxazolyl]benzenesulfonamide;

[0323]4-[4-phenyl-2-[[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0324] 4-[4-phenyl-2-[[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0325]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0326]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]-1,2,3-triazol-4-ylmethyl-5-]oxazole;

[0327]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0328]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl[benzenesulfonamide;

[0329]4-[4-phenyl-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0330]4-[4-phenyl-2-[[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiophenyl]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0331]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yloxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0332]4-[4-phenyl-2-[[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-ylmethoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0333]4-[4-phenyl-2-[[6-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-2-ylmethoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0334]4-[4-phenyl-2-[[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)benzyloxy]-1,2,3-triazol-4-ylmethoxy-5-]-5-oxazolyl]benzenesulfonamide;

[0335]4-[4-phenyl-2-[[2-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-ylmethoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0336] 4-[4-phenyl-2-[[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenoxy]-1,2,3-triazol-4-ylmethyl-5-]-5-oxazolyl]benzenesulfonamide;

[0337]4-[4-phenyl-2-[[3-(3,4,5,-tetrahydro-2H-pyran-4-yl)]E-oximinomethyl]phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0338]4-[4-methyl-2-[[[3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)]Z-oximinomethyl]phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0339]4-[4-phenyl-2-[[E-O-methyl-[3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)]oximinomethyl]phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0340]4-[4-phenyl-2-[[Z-O-methyl-[3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)oximinomethyl]phenoxy]acetyl]-5-oxazolyl]benzenesulfonamide;

[0341]4-[4-phenyl-2-[3-[[3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)]Z-oximinomethyl]phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0342]4-[4-phenyl-2-[3-[[3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)]E-oximinomethyl]phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0343]4-[4-phenyl-2-[3-[E-O-methyl-[3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)]oximinomethyl]phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0344]4-[4-phenyl-2-[3-[Z-O-methyl-[3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)]oximinomethyl]phenoxy]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0345]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0346]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-(3,4,5,-tetrahydro-4-methoxy-2H-pyran-4-yl)phenyl]propyn-1-yl]oxazole;

[0347]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0348]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0349]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0350]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4yl)thiazol-4-yl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0351] 4-[4-phenyl-2-[3-[3-flouro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.3.1]octanyl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0352]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0353]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenyl]propyn-1-yl]oxazole;

[0354]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0355]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-y]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0356]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0357]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-yl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0358] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide;

[0359]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-4-yl)phenyl]propyl]-5-oxazolyl]benzenesulfonamide;

[0360]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenyl]propyl]oxazole;

[0361]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenyl]propyl]y-5-oxazolyl]benzenesulfonamide;

[0362]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)pyridin-3-yl]propyl]-5-oxazolyl]benzenesulfonamide;

[0363]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenyl]propyl]-5-oxazolyl]benzenesulfonamide;

[0364]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)thiazol-4-yl]propyl]-5-oxazolyl]benzenesulfonamide;

[0365] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-methoxy-6,8-dioxabicyclo[3.2.1]octanyl)phenyl]propyl]-5-oxazolyl]benzenesulfonamide;

[0366]4-[4-phenyl-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenyl]propyl]-5-oxazolyl]benzenesulfonamide;

[0367]4-phenyl-5-[4-[4-(methylsulfonyl)phenyl]-2-[3-[3-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenyl]propyl]oxazole;

[0368]4-[4-phenyl-2-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenyl]propyl]-5-oxazolyl]benzenesulfonamide;

[0369]4-[4-phenyl-2-[3-[5-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)pyridin-3-yl]propyl]-5-oxazolyl]benzenesulfonamide;

[0370]4-[4-phenyl-2-[3-[3-(2,6-dimethyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)phenyl]propyl]-5-oxazolyl]benzenesulfonamide;

[0371]4-[4-phenyl-2-[3-[2-(3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-4-yl)thiazol-4-yl]propyl]-5-oxazolyl]benzenesulfonamide;and

[0372] 4-[4-phenyl-2-[3-[3-fluoro-5-(1S,5R3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)phenyl]propyn-1-yl]-5-oxazolyl]benzenesulfonamide.

[0373] The term “hydrido” denotes a single hydrogen atom (H). Thishydrido radical may be attached, for example, to an oxygen atom to forma hydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical. Where used, either alone orwithin ocher terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl”and “hydroxyalkyl”, the term “alkyl” embraces linear or branchedradicals having one to about twenty carbon atoms or, preferably, one toabout towel carbon atoms. More preferred alkyl radicals are “loweralkyl” radicals having one to about ten carbon atoms. Most preferred arelower alkyl radicals having one to about six carbon atoms. Example ofsuch radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkylradicals are “lower alkenyl” radicals having two to about six carbonatoms. Examples of alkenyl radicals include ethenyl, propenyl, alkenyl,propenyl, butenyl and 4-methylbutenyl. The term “alkynyl” denotes linearor branched radicals having two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkynylradicals are “lower alkynyl” radicals having two to about ten carbonatoms. Most preferred are lower alkynyl radicals having two to about sixcarbon atoms. alkynyl radicals of such radicals include propargyl,butynyl, and the like. The terms “alkenyl”, “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations. The term “cycloalkyl” embraces saturatedcarbocyclic radicals having three to twelve carbon atoms. More preferredcycloalkyl radicals are “lower cycloalkyl” radicals having three toabout eight carbon atoms. Examples of such radicals include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. The term. “cycloalkenyl”embraces partially unsaturated carbocyclic radicals having three totwelve carbon atoms. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.The term “halo” means halogens such as fluorine, chlorine, bromine oriodine. The term “haloalkyl” embraces radicals wherein any one or moreof the alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1-6 carbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. The term“hydroxyalkyl” embraces linear or branched alkyl radicals having one toabout ten carbon atoms any one of which may be substituted with one ormore hydroxyl radicals. More preferred hydroxyalkyl radicals are “lowerhydroxyalkyl” radicals having one to six carbon atoms and one or morehydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxpropyl, hydroxybutyl and hydroxyhexyl. The term“cyanoalkyl” embraces linear or branched alkyl radicals having one toabout ten carbon atoms any one of which may be substituted with one ormore cyano radicals. More preferred cyanoalkyl radicals are “lowercyanoalkyl” radicals having one to six carbon atoms and one or morecyano radicals. Examples of such radicals include cyanomethyl,cyanoethyl, cyanopropyl, cyanobutyl and cyanohexyl. The terms “alkoxy”and “alkyloxy” embrace linear or branched oxy-containing radicals eachhaving alkyl portions of one to about ten carbon atoms. More preferredalkoxy radicals are “lower alkoxy” radicals having one to six carbonatoms. Examples of such radicals include methoxy, ethoxy, propoxy,butoxy and tert-butoxy. The term “alkoxyalkl” embraces alkyl radicalshaving one or more alkoxy radicals attached to the alkyl radical, thatis, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The “alkoxy”radicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide haloalkoxy radicals, or withhydroxyl radicals to from “hydroxyalkyloxy” radicals. More preferredhaloalkoxy radicals are “lower haloalkoxy” radicals having one to sixcarbon atoms and one or more halo radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy. More preferred hydroxyalkyloxy radicalsare “lower hydroxyalkyloxy” radicals having alkyl poriotns of 1 to 6carbons. The term “alkenyloxy” embraces radicals having alkenyl portionsof two to about ten carbon atoms attached to an oxygen atom. Morepreferred alkenyloxy radicals are “lower alkenyloxy” radicals having twoto six carbon atoms. The term “alkynyloxy” embraces radicals havingalkynyl portions of two to about ten carbon atoms attached to an oxygenatom. More preferred alkynyloxy radicals are “lower alkynyloxy” radicalshaving two to six carbon atoms. Examples of such lower alkynyloxyradicals include propynyloxy, and butynyloxy. The term “aryl”, alone orin combination, means a carbocyclic aromatic system containing one, twoor three rings wherein such rings may be attached together in a pendentmanner or may be fused. The term “aryl” embraces aromatic radicals suchas phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Arylmoieties may also be substituted at a substitutable position with one ormore substituents selected independently from alkyl, alkoxyalkyl,alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano,carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. The term“heterocyclyl” embraces saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, where the heteroatoms may beselected from nitrogen, sulfur and oxygen. Examples of saturatedheterocyclyl radicals include saturated 3 to 6-membered heteromonocylicgroup containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. The term “heteroaryl”embraces unsaturated heterocyclyl radicals. Examples of unsaturatedheterocyclyl radicals, also termed “heteroaryl” radicals includeunsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.)tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturatedcondensed heterocyclyl group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term alsoembraces radicals where heterocyclyl radicals are fused with arylradicals. Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like. Said “heterocyclyl group” may have 1 to 3substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino andalkylamino. The term “alkylthio” embraces radicals containing a linearor branched alkyl radical, of one to about ten carbon atoms attached toa divalent sulfur atom. More preferred alkylthio radicals are “loweralkylthio” radicals having alkyl radicals of one to six carbon atoms.Examples of such lower alkylthio radicals are methylthio, etnylthio,propylthio, butylthio and hexylthio. The term “alkylthioalkyl” embracesradicals containing an alkylthio radical attached through the divalentsulfur atom to an alkyl radical of one to about ten carbon atoms. Morepreferred alkylthioalkyl radicals are “lower alkylthioalkyl” radicalshaving alkyl radicals of one to six carbon atoms. Examples of such loweralkylthioalkyl radicals include methylthiomethyl. The term“oximinoalkoxy” embraces alkyloxy radicals having one to about tencarbon atoms any one or which may be substituted with one or moreoximino radicals (—C═NOH). More preferred oximinoalkoxy radicals are“lower oximinoalkoxy” radicals having alkoxy radicals containing one tosix carbon atoms. Examples of such radicals include oximinomethoxy,oximinopropoxy, and oximinobutoxy. The term “oximinoalkoxyalkyl”embraces alkyloxyalkyl radicals with alkyl and portions having one toabout ten carbon atoms any one of which may be substituted with anoximino radical (—C═NOH). More preferred oximinoalkoxyalkyl radicals are“lower oximinoalkoxyalkyl” radicals having alkyl radicals containing oneto six carbon atoms. The terms “(alkyl)oximinoalkoxyalkyl” and“(alkyl)oximinoalkoxy” embrace oximinoalkoxyalkyl and oximinoalkoxyradicals, as defined above, where the oximino portion is substituted onthe oxygen atom with alkyl radicals having one to about ten carbonatoms. More preferred oximinoalkoxyalkyl radicals are “lower“(alkyl)oximinoalkoxyalkyl” and “lower (alkyl)oximinoalkoxy” radicalshaving alkyl radicals containing one to six carbon atoms. The term“alkenylthio” embraces radicals containing a linear or branched alkenylradical, of two to about ten carbon atoms attached to a divalent sulfuratom. More preferred alkenylthio radicals are “lower alkenylthio”radicals having alkenyl radicals of two to six carbon atoms. The term“alkynylthio” embraces radicals containing a linear or branched alkynylradical, of two to about ten carbon atoms attached to a divalent sulfuratom. More preferred alkynylthio radicals are “lower alkynylthio”radicals having alkynyl radicals of two to six carbon atoms. The term“alkylsulfinyl” embraces radicals containing a linear or branched alkylradical, of one to ten carbon atoms, attached to a divalent —S(═O)—radical. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl”radicals having alkyl radicals of one to six carbon atoms. Examples ofsuch lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl,butylsulfinyl and hexylsulfinyl. The term “sulfonyl”, whether used aloneor linked to other terms such as alkylsulfonyl, denotes respectivelydivalent radicals —SO₂—. “Alkylsulfonyl” embraces alkyl radicalsattached to a sulfonyl radical, where alkyl is defined as above. Morepreferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicalshaving one to six carbon atoms. Examples of such lower alkylsulfonylradicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The“alkylsulfonyl” radicals may be further substituted with one or morehalo atoms, such as fluoro, chloro or bromo, to providehaloalkylsulfonyl radicals. The terms “sulfamyl”, “aminosulfonyl” and“sulfonamidyl” denote NH₂O₂S—. The term “acyl” denotes a radicalprovided by the residue after removal of hydroxyl from an organic acid.Examples of such acyl radicals include alkanoyl and aroyl radicals.Examples of such lower alkanoyl radicals include formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,trifluoroacetyl. The term “carbonyl”, whether used alone or with otherterms, such as “alkoxycarbonyl”, denotes —(C═O)—. The term “aroyl”embraces aryl radicals with a carbonyl radical as defined above.Examples of aroyl include benzoyl, naphthoyl, and the like and the arylin said aroyl may be additionally substituted. The terms “carboxy” or“carboxyl”, whether used alone or with other terms, such as“carboxyalkyl”, denotes —CO₂H. The term “carboxyalkyl” embraces alkylradicals substituted with a carboxy radical. More preferred are “lowercarboxyalkyl” which embrace lower alkyl radicals as defined above, andmay be additionally substituted on the alkyl radical with halo. Examplesof such lower carboxyalkyl radicals include carboxymethyl, carboxyethyland carboxypropyl. The term “alkoxycarbonyl” means a radical containingan alkoxy radical, as defined above, attached via an oxygen atom to acarbonyl radical. More preferred are “lower alkoxycarbonyl” radicalswith alkyl porions having 1 to 6 carbons. Examples of such loweralkoxycarbonyl (ester) radicals include substituted or unsubstitutedmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl andhexyloxycarbonyl. The terms “alkylcarbonyl”, “arylcarbonyl” and“aralkylcarbonyl” include radicals having alkyl, aryl and aralkylradicals, as defined above, to a carbonyl radical. Examples of suchradicals include substituted or unsubstituted methylcarbonyl,ethylcarbonyl, phenylcarbonyl and benzylcarbonyl. The term “aralkyl”embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in saidaralkyl may be additionally substituted with halo, alkyl, alkoxy,halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl areinterchangeable. The term “heteroaralkyl” embracesheteroaryl-substituted alkyl radicals, such as pyridylmethyl,quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. Theheteroaryl in said heteroaralkyl may be additionally substituted withhalo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term “aralkoxy”embraces aralkyl radicals attached through an oxygen atom to otherradicals. The term “aralkoxyalkyl” embraces aralkoxy radicals attachedthrough an oxygen atom to an alkyl radical. The term “aralkylthio”embraces aralkyl radicals attached to a sulfur atom. The term“aralkylthioalkyl” embraces aralkylthio radicals attached through asulfur atom to an alkyl radical. The term “heteroaralkoxy” embracesheteroaralkyl radicals attached through an oxygen atom to otherradicals. The term “heteroaralkylthio” embraces heteroaralkyl radicalsattached through a sulfur atom to other radicals. The term “aminoalkyl”embraces alkyl radicals substituted with amino radicals. More preferredare “lower aminoalkyl” radicals. Examples of such radicals includeaminomethyl, aminoethyl, and the like. The term “alkylamino” denotesamino groups which have been substituted with one or two alkyl radicals.Preferred are “lower N-alkylamino” radicals having alkyl porions having1 to 6 carbon atoms. Suitable lower alkylamino may be mono ordialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like. The term “cycloalkylamino” denotes aminogroups which have been substituted with one or two cycloalkyl radicals,as defined above. The term “arylamino” denotes amino groups which havebeen substituted with one or two aryl radicals, such as N-phenylamino.The “arylamino” radicals may be further substituted on the aryl ringportion of the radical. The term “aralkylamino” embraces aralkylradicals attached through an nitrogen atom to other radicals. The terms“N-arylaminoalkyl” and “N-aryl-N-alkyl-aminoalkyl” denote amino groupswhich have been substituted with one aryl radical or one aryl and onealkyl radical, respectively, and having the amino group attached to analkyl radical. Examples of such radicals include N-phenylaminomethyl andN-phenyl-N-methylaminomethyl. The term “aminocarbonyl” denotes an amidegroup of the formula —C(═O)NH₂. The term “alkylaminocarbonyl” denotes anaminocarbonyl group which has been substituted with one or two alkylradicals on the amino nitrogen atom. Preferred are“N-alkylaminocarbonyl” “N,N-dialkylaminocarbonyl” radicals. Morepreferred are “lower N-alkylaminocarbonyl” “lowerN,N-dialkylaminocarbonyl” radicals with lower alkyl portions as definedabove. The term “alkylaminocarbonylhaloalkyl” denotes an aminocarbonylgroup which has been substituted with one or two alkyl radicals on theamino nitrogen atom, attached to an haloalkyl radical. Preferred are“N-alkylaminocarbonylhaloalkyl” “N,N-alkylaminocarbonylhaloalkyl”radicals. More preferred are “lower N-alkylaminocarbonylhaloalkyl”“lower N,N-alkylaminocarbonylhaloalkyl” radicals with lower alkyl andlower haloalkyl portions as defined above. The term “alkylaminoalkyl”embraces radicals having one or more alkyl radicals attached to anaminoalkyl radical. The term “aryloxyalkyl” embraces radicals having anaryl radicals attached to an alkyl radical through a divalent oxygenatom. The term “arylthioalkyl” embraces radicals having an aryl radicalsattached to an alkyl radical through a divalent sulfur atom.

[0374] When the above radicals are included as linker moiety “Y” inFormulas I-II, such radicals are divalent radicals. In addition, theorientation of the radicals between “A” and “Ar” are reversible. Forexample, the term “alkylthio” represents both —CH₂S— and —SCH₂—, and“carbonylmethyloxy” represents both —C(O)CH₂O— and —OCH₂C(O)—. For termssuch as aralkyl, and heteroarylalkyl, the moiety may be linked to “A”and “Ar” through a divalent alkyl radical, or through the alkyl radicalat one end and the aryl or heteroaryl portion at the other. The use ofheterocyclyl and aryl moieties includes divalent attachment atsubstitutable sites. The use of a substituted amine group, does notinclude attachment through a divalent nitrogen atom (i.e., —N(CH₃)—) butinstead (—N(H)CH₂—).

[0375] The present invention comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of FormulasI-II in association with at least one pharmaceutically-acceptablecarrier, adjuvant or diluent.

[0376] The present invention also comprises a method of treatinginflammation or inflammation-associated disorders in a subject, themethod comprising treating the subject having or susceptible to suchinflammation or disorder, with a therapeutically-effective amount of acompound of Formulas I-II. The method includes prophylactic or chronictreatment, especially in the case of arthritis and other inflammatoryconditions which can lead to deterioration in the joints.

[0377] Also included in the family of compounds of Formula I are thestereoisomers and tautomers thereof. Compounds of the present inventioncan possess one or more asymmetric carbon atoms and are thus capable ofexisting in the form of optical isomers as well as in the form ofracemic or nonracemic mixtures thereof. Accordingly, some of thecompounds of this invention may be present in racemic mixtures which arealso included in this invention. The optical isomers can be obtained byresolution of the racemic mixtures according to conventional processes,for example by formation of diastereoisomeric salts by treatment with anoptically active acid or base. Examples of appropriate acids aretartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting an amine functionalityof precursors to compounds of Formula I with an optically pure acid inan activated form or an optically pure isocyanate. Alternatively,diastereomeric derivatives can be prepared by reacting a carboxylfunctionality of precursors to compounds of Formula I with an opticallypure amine base. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a calt.

[0378] Also included in the family of compounds of Formula I are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic,cyclohexylaminosulfonic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formula I include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. All of these salts may be prepared byconventional means from the corresponding compound of Formula I byreacting, for example, the appropriate acid or base with the compound ofFormula I.

General Synthetic Procedures

[0379] The compounds of the invention can be synthesized according tothe following procedures of Schemes I-XXIII, wherein the R¹-R⁹substituents are as defined for Formula I-II, above, except wherefurther noted.

[0380] Synthetic Scheme I shows the preparation of sulfonylphenylderivatives 3, where one of Z or W is a leaving group. A substitutedaromatic or heteroaryl 2, such a tetrahydropyran substituted aryl, and abase such as anhydrous potassium carbonate are dissolved in anhydroussolvent such as DMF. A solution of sulfonylphenyl derivative 1 inanhydrous DMF is added and stirred at room temperature to provide thesulfonylphenyl derivatives 3.

[0381] Synthetic Scheme II shows the preparation or pyrazole compoundsembraced by Formula I where R is Ar or Z (as defined in Scheme I), andR^(a) is a radical defined above for the substituents optionallysubstituted on A. In step 1, ketone 4 is treated with a base, preferablyNaOMe or NaH, and an ester, or ester equivalent, to form theintermediate diketone 5 (in the enol form) which is used without furtherpurification. In step 2, diketone 5 in an anhydrous protic solvent, suchas absolute ethanol or acetic acid, is treated with the hydrochloridesalt or the free base of a substituted hydrazine at reflux to afford amixture of pyrazoles 6 and 7. Recrystallization from diethylether/hexane or chromatography affords 6 usually as a solid. Similarpyrazoles can be prepared by methods described in U.S. Pat. Nos.4,146,721, 5,051,518, 5,134,142 and 4,914,121 which are incorporated byreference.

[0382] Scheme III shows the four step procedure for forming pyrazoles 11of the present invention (where R^(b) is alkyl) from ketones 8. In step1, ketone 8 is reacted with a base, such as lithiumbis(trimethylsilyl)amide or lithium diisopropylamide (LDA) to form theanion. In step 2, the anion is reacted with an acetylating reagent toprovide diketone 9. In step 3, the reaction of diketone 9 with hydrazineor a substituted hydrazine, gives pyrazole 10. In step 4, the pyrazole10 is oxidized with an oxidizing reagent, such as Oxone® (potassiumperoxymonosulfate), 3-chloroperbenzoic acid (MCPBA) or hydrogenperoxide, to give a mixture of the desired3-(alkylsulfonyl)phenyl-pyrazole 11 and the5-(alkylsulfonyl)phenyl-pyrazole isomer. The desired pyrazole 11,usually a white or pale yellow solid, is obtained in pure form either bychromatography or recrystallization.

[0383] Alternatively, diketone 9 can be formed from ketone 8 bytreatment with a base, such as sodium hydride, in a solvent, such asdimethylformamide, and further reacting with a nitrile to form anaminoketone. Treatment of the aminoketone with acid forms the diketone9. Similar pyrazoles can be prepared by methods described in U.S. Pat.No. 3,984,431 which is incorporated by reference.

[0384] Diaryl/heteroaryl thiophenes (where T is S, and R^(b) is alkyl)can be prepared by the methods described in U.S. Pat. Nos. 4,427,693,4,302,461, 4,381,311, 4,590,205, and 4,820,827, and PCT documents WO95/00501 and WO94/15932, which are incorporated by reference. Similarpyrroles (where T is N), furanones and furans (where T is O) can beprepared by methods described in PCT documents WO 95/00501 andWO94/15932.

[0385] Diaryl/heteroaryl oxazoles can be prepared by the methodsdescribed in U.S. Pat. Nos. 3,743,656, 3,644,499 and 3,647,850, and PCTdocuments WO 95/00501 and WO94/15932, which are incorporated byreference.

[0386] Diaryl/heteroaryl isoxazoles can be prepared by the methodsdescribed in PCT documents WO92/05162, and WO92/19604, and EuropeanPublication EP 26928 which are incorporated by reference. Sulfonamides27 can be formed from the hydrated isoxazole 26 in a two step procedure.First, hydrated isoxazole 26 is treated at about 0° C. with two or threeequivalents of chlorosulfonic acid to form the corresponding sulfonylchloride. In step two, the sulfonyl chloride thus formed is treated withconcentrated ammonia to provide the sulfonamide derivative 27.

[0387] Scheme VII shows the three step preparation of the substitutedimidazoles 32 of the present invention. In step 1, the reaction ofsubstituted nitrites (R¹CN) 28 with primary phenylamines 29 in thepresence of alkylaluminum reagents such as trimethylaluminum,triethylaluminum, dimethylaluminum chloride, diethylaluminum chloride inthe presence of inert solvents such as toluene, benzene, and xylene,gives amidines 30. In step 2, the reaction of amidine 30 with2-haloketones (where X is Br or Cl) in the presence of bases, such assodium bicarbonate, potassium carbonate, sodium carbonate, potassiumbicarbonate or hindered tertiary amines such asN,N′-diisopropylethylamine, gives the 4,5-dihydroimidazoles 31 (whereR^(b) is alkyl, R^(c) is hydroxyl and R^(d) is hydrido). Some of thesuitable solvents for this reaction are isopropanol, acetone anddimethylformamide. The reaction may be carried out at temperatures ofabout 20° C. to about 90° C. In step 3, the 4,5-dihydroimidazoles 31 maybe dehydrated in the presence of an acid catalyst such as4-toluenesulfonic acid or mineral acids to form the 1,2-disubstitutedimidazoles 32 of the invention. Suitable solvents for this dehydrationstep are e.g., toluene, xylene and benzene. Trifluoroacetic acid can beused as solvent and catalyst for this dehydration step.

[0388] In some cases (e.g., where YR=methyl or phenyl) the intermediate31 may not be readily isolable. The reaction, under the conditionsdescribed above, proceeds to give the targeted imidazoles directly.

[0389] Similarly, imidazoles can be prepared having the sulfonylphenylmoiety attached at position 2 and R¹ attached at the nitrogen atom atposition 1. Diaryl/heteroaryl imidazoles can be prepared by the methodsdescribed in U.S. Pat. Nos. 4,822,805, and PCT document WO 93/14082,which are incorporated by reference.

[0390] The subject imidazole compounds 39 of this invention may besynthesized according to the sequence outlined in Scheme VIII. Aldehyde33 may be converted to the protected cyanohydrin 34 by reaction with atrialkylsilyl cyanide, such as trimethylsilyl cyanide (TMSCN) in thepresence of a catalyst such as zinc iodide (ZnI₂) or potassium cyanide(KCN). Reaction of cyanohydrin 34 with a strong base followed bytreatment with benzaldehyde 35 (where R² is alkyl) and using both acidand base treatments, in that order, on workup gives benzoin 36. Examplesof strong bases suitable for this reaction are lithium diisopropylamide(LDA) and lithium hexamethyldisilazane. Benzoin 36 may be converted tobenzil 37 by reaction with a suitable oxidizing agent, such as bismuthoxide or manganese dioxide, or by a Swern oxidation using dimethylsulfoxide (DMSO) and trifluoroacetic anhydride. Benzil 37 may beobtained directly by reaction of the anion of cyanohydrin 34 with asubstituted benzoic acid halide. Any of compounds 36 and 37 may be usedas intermediates for conversion to imidazoles 38 (where R² is alkyl)according to chemical procedures known by those skilled in the art anddescribed by M. R. Grimmett, “Advances in Imidazole Chemistry” inAdvances in Heterocyclic Chemistry, 12, 104 (1970). The conversion of 37to imidazoles 38 is carried out by reaction with ammonium acetate and anappropriate aldehyde (RYCHO) in acetic acid. Benzoin 36 may be convertedto imidazoles 38 by reaction with formamide. In addition, benzoin 36 maybe converted to imidazoles by first acylating with an appropriate acylgroup (RYCO—) and then treating with ammonium hydroxide. Those skilledin the art will recognize that the oxidation of the sulfide (where R² ismethyl) to the sulfone may be carried out at any point along the waybeginning with compounds 35, and including oxidation of imidazoles 38,using, for examples, reagents such as hydrogen peroxide in acetic acid,m-chloroperoxybenzoic acid (MCPBA) and potassium peroxymonosulfate(OXONE®).

[0391] Diaryl/heteroaryl imidazoles can be prepared by the methodsdescribed in U.S. Pat. Nos. 3,707,475, 4,686,231, 4,503,065, 4,472,422,4,372,964, 4,576,958, 3,901,908, European publication EP 372,445, andPCT document WO 95/00501, which are incorporated by reference.

[0392] Diaryl/heteroaryl cyclopentenes can be prepared by the methodsdescribed in U.S. Pat. No. 5,344,991, and PCT document WO 95/00501,which are incorporated by reference.

[0393] Similarly, Synthetic Scheme X shows the procedure for thepreparation of 1,2-diarylbenzene antiinflammatory agents 47 from2-bromo-biphenyl intermediates 46 (prepared similar to that described inSynthetic Scheme IX) and the appropriate substituted phenylboronicacids. Using a coupling procedure similar to the one developed by Suzukiet al. [Synth. Commun., 11, 513 (1981)], intermediates 46 are reactedwith the boronic acids in toluene/ethanol at reflux in the presence of aPd^(o) catalyst, e.g., tetrakis(triphenylphosphine) palladium (0), and2M sodium carbonate to give the corresponding 1,2-diarylbenzeneantiinflammatory agents 47 of this invention.

[0394] Diaryl/heteroaryl thiazoles can be prepared by the methodsdescribed in U.S. Pat. No. 4,051,250, 4,632,930, European Application EP592,664, and PCT document WO 95/00501, which are incorporated byreference. Isothiazoles can be prepared as described in PCT document WO95/00501.

[0395] Diary/heteroaryl pyridines can be prepared by the methodsdescribed in U.S. Pat. Nos. 5,169,857, 4,011,328, and 4,533,666, whichare incorporated by reference. For example, Synthetic Scheme XII showsthe procedure used to prepare 3-alkylcarbonylaminoalkyl pyridineantiinflammatory agents 53, 3-haloalkyl pyridine antiinflammatory agents55, 3-hydroxyalkyl pyridine antiinflammatory agents 56, heteroatomsubstituted 3-alkyl pyridine antiinflammatory agents 58 and3-aryloxyalkyl pyridine antiinflammatory agents 59 from thecorresponding carbonitriles 51. The 3-alkylcarbonylaminoalkyl pyridineantiinflammatory agents 53 (where R′ is alkyl) are prepared in a twostep procedure from the carbonitriles 51. In step one, the carbonitrile51 is reduced using reducing agents, such as diisobutyl aluminum hydride(DIBAL) in a solvent such as toluene or boranes in a solvent such astetrahydrofuran, at room temperature or reflux to form the aminoalkylpyridine 52. Additional reducing reagent may be added to the solution.In step two, an acid chloride is added to the aminoalkyl pyridine 52 ina solvent such as ethyl ether or tetrahydrofuran and stirred to form thealkylcarbonylaminoalkyl pyridines 53. The 3-haloalkyl pyridineantiinflammatory agents 55 are prepared in a two step procedure from thecarbonitriles 51. In step one, the carbonitriles 51 are reduced usingagents, such as diisobutyl aluminum hydride (DIBAL) in a solvent such astoluene, at room temperature to form the aldehydes 54. The3-hydroxyalkyl pyridines 56 also can be isolated from this reaction. Instep two, a halogenating agent, such as diethylamino sulfur trifluoride(DAST) is added to the aldehyde 54 to form the haloalkyl pyridines 55.Reduction of aldehydes 54 with agents such as diisobutyl aluminumhydride (DIBAL) followed by methanol and water in methanol to yield the3-hydroxyalkyl pyridines 56. Compound 56 is convertible to alkoxyalkyland aralkoxyalkyl compounds 59 by sequential treatment first with a baseand then with an alkyl or aralkyl halide. An example of a suitable baseis sodium hydride. Examples of alkyl and aralkyl halides are methyliodide and benzyl chloride. Alternatively, compound 56 may be convertedto the haloalkyl compound 57 using a suitable halogenating agent, suchas thionyl chloride. Under such circumstances, the hydrochloride saltmay be isolated. This in turn may be converted to compounds 58 byreaction with the appropriate alcohol, thiol, or amine. It may beadvantageous to carry out this reaction in the presence of a base.Examples of suitable alcohols are methanol, ethanol, benzyl alcohol andphenol. Examples of suitable thiols are n-butyl mercaptan, benzylthioland thiophenol. Examples of suitable amines are dimethylamine,benzylamine, N-methylbenzylamine, aniline, N-methylaniline anddiphenylamine. Examples of suitable bases are sodium hydride andpotassium carbonate. Alternatively, amines are accessible by reaction ofaldehyde 54 with a primary or secondary amine in the presence of areducing agent. Examples of suitable primary amines are methyl amine andethylamine. An example of a suitable secondary amine is dimethylamine.Suitable reducing agents include sodium cyanoborohydride and sodiumborohydride.

[0396] Scheme XIII shows a method to form the alkylsulfonylphenylsubstituted heterocycles 61 of the current invention by oxidation ofalkylthio or alkylsulfinyl derivatives 60. Aqueous hydrogen peroxide(30%) is added to a suspension of a (methylthio)phenyl substitutedheterocycle 60 in acetic acid. The mixture is stirred while heating toabout 100° C. for about 2 hours. Alternatively, m-chloroperoxybenzoicacid (MCPBA), and other oxidizing agents [potassium peroxymonosulfate(OXONE®)] can be used to form the sulfonyl radicals 61.

[0397] Synthetic Scheme XIV shows the three step procedure used toprepare sulfonamide antiinflammatory agents 63 and the two stepprocedure used to prepare fluoromethyl sulfone antiinflammatory agents64 from their corresponding methyl sulfones 62. In step one, THFsolutions of the methyl sulfones 62 at −78° C. are treated with analkyllithium reagent, e.g., methyllithium, n-butyllithium, etc. In steptwo, the anions generated in step one are treated with an organoborane,e.g., triethylborane, tributylborane, etc., at −78° C. then allowed towarm to ambient temperature prior to stirring at reflux. In step three,an aqueous solution of sodium acetate and hydroxylamine-O-sulfonic acidis added to provide the corresponding sulfonamide antiinflammatoryagents 63 of this invention. As an alternative to the borane chemistryfound in step two above, the base treated sulfone is reacted with analkylsilane, such as (iodomethyl)trimethylsilane or (chloromethyl)trimethylsilane, at room temperature to give a silylalkylsulfone. Thesilylalkylsulfone is converted to a sulfinic acid salt by heating toabout 90° C. with tetrabutylammonium fluoride. Treatment proceeds as instep three above to produce the sulfonamide.

[0398] Alternatively, the anion solutions generated in step one may bewarmed to 0° C. and treated with N-fluorodibenzenesulfonamide to providethe corresponding fluoromethyl sulfone antiinflammatory agents 64 ofthis invention.

[0399] Synthetic Scheme XV shows the four step procedure used to prepareanti-inflammatory compound of Formula II. In step one, a dichloromethanesolution of1-(substitutedphenyl)-2-hydroxy-2-[4-(methylsulfonyl)phenyl]ethanone 65(described in U.S. Pat. No. 5,380,738) is treated with benzyloxyacetylchloride in the presence of pyridine base to provide2-benxyloxymethyl-4-(substitutedphenyl)-5-[4-(methylsulfonyl)phenyl]oxazole66 in good yield. In step two, the benzyloxy group is removed byhydrogenolysis in the presence of a catalytic amount of 10% palladium oncharcoal to provide the hydroxymethyl compound 67. In step three, thehydroxymethyl compound 67 is treated with a solution of methanesulfonylchloride in the presence of triethylamine base to produce the unstablemesylate 68 that is used directly in the next step. In step four, amixture of the mesylate and a 3,4,5,6-tetrahydro-2H pyran indimethylformamide (DMF) is treated with potassium carbonate to effectether formation and provide the anti-inflammatory agents 69 (where R^(f)is halo, alkoxy, or alkyl) of the present invention.

[0400] Synthetic Scheme XVI shows the four step procedure that is usedto prepare anti-inflammatory compound of Formula II. In step one,benzoin 70 is mixed with ethyl carbarmate (urethane) and heated toreflux to provide oxazolone 71 in high yield. In step two, oxazolone 71is treated with a mixture of phosphorus oxychloride and triethylaminebase to produce 2-chloro-5-phenyloxazole 72. In step three,2-chloro-5-phenyloxazole 72 is treated first with chlorosulfonic acid toeffect regioselective chlorosulfonation, followed by treatment withaqueous ammonia provides 2-chloro-5-(4-sulfonamido)phenyloxazole 73 inhigh yield. In step four, 2-chloro-5-(4-sulfonamido)phenyloxazole 73 anda tetrahydro-2H-pyran-substituted phenol is treated with potassiumcarbonate to effect ether formation and provide the anti-inflammatoryagents of the present invention 74.

[0401] Synthetic Scheme XVII shows a four step method of making thepyrazole phenylethers 79 of the present invention. In step 1, the dione76 is formed from ketone 75 through the addition of a base, such aslithium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA),followed by reacting with an appropriate acetylating reagent, such as(CO₂CH₃)₂. Treatment of the dione 76 with a phenylhydrazine yields thepyrazole ester 77. The pyrazole ester 77 is first treated with base tohydrolyze the ester and is then reduced to the alcohol 78 by treatmentwith borane in THF. In step four, the alcohol 78 is treated withmethanesulfonyl chloride in the presence of triethylamine base toproduce the unstable mesylate that is directly reacted with a3,4,5,6-tetrahydro-2H pyran in dimethylformamide and K₂CO₃ to effectether formation and provide the anti-inflammatory agents 79 of thepresent invention.

[0402] Scheme XVIII shows a procedure for forming an alkynyl oxazole 84(where R² is amino), similar to that shown in Scheme V above. The ketonesulfonamide 81 is formed from ketone 80 through chlorosulfonation andammonolysis with ammonium hydroxide in a solvent such as acetone. Theketone sulfonamide 81 is halogenated, such as with HBr in acetic acidand bromine, to form the haloketone sulfonamide 82. Substitution withbutynoic acid in the presence of K₂CO₃, a crown ether, such as18-crown-6, and dimethylacetamide (DMA) yields the alkynyl ketoester 83.Conversion of the alkynyl ester 83 to the alkynyl oxazole 84 proceeds aspreviously described in Scheme V.

[0403] Synthetic Scheme XIX shows the procedures for formingheterocycloalkynylethers 87, heterocyclotriazole ethers 88 andheterocycloalkylethers 89, from the corresponding alkynes 85. Thealkynes 85 are halogenated such as with N-bromosuccinimide (NBS) and2,2′-azobis(2-methylpropionitrile) (AIBN) to form the haloalkynes 86.Substitution with the appropriate aryl or aralkyl alcohols in thepresence of potassium carbonate yields the alkynyl ethers 87 of thepresent invention. The alkynylethers 87 can be converted toheterocyclo-containing spacers 88 by treatment withazidotrimethylsilane, followed by acid. Alternatively, the alkynylethers87 can be reduced, such as with hydrogen in the presence of catalyst,such as palladium, to yield the heterocycloalkylethers 89.

[0404] Scheme XX shows another method of forming the alkynylethers 92,alkylethers 93, alkenylethers 94 and the diols 95 of the presentinvention from the appropriate alkynes 90. In Step one, the alkynes 90(where P is a protecting group such as tetrahydropyranyl, trialkylsilyl,tert-butyldimethylsilyl or diphenylalkylsilyl) are acid treated to formthe alkynyl alcohols 91. Substitution of the alcohol 91 with aralkylhalides or heteroaryl halides in the presence of1,8-diazabicyclo[5.4.0]undecane (DBU) yields the propynylethers 92 ofthe present invention. Reduction of the alkynylethers 92 with hydrogenin the presence of metal catalyst yields the alkylethers 93.Alternatively, treatment with diimide reduces the alkynylethers 92 tothe alkenylethers 94. Oxidation of the alkenylether 94, such as withosmium tetraoxide and hydrogen peroxide, yields the diols 95 of thepresent invention.

[0405] Additional antiinflammatory agents containing various substitutedalkylether spacer radicals including carbonylalkylethers 98,aminoalkylethers 100, hydroxyalkylethers 101, oxyiminoalkylethers 99,and amidoalkylethers 102, can be prepared from ketones 96, by theprocedures shown in Scheme XXI. The ketones 96 are halogenated to formhalomethylketone 97 such as by treatment with NBS in the presence ofAIBN. Substitution of appropriate alcohols with the halides 97 in thepresence of base, such as potassium carbonate, generates theketoalkylethers 98. The ketoalkylethers 98 can be converted to theoxyimino-containing spacers 99 (where R^(g) is alkyl) by treatment withsubstituted oxyamines, such as hydroxylamine. Hydroxyalkyl spacers 101can be prepared by reducing the carbonyl in the ketoalkylethers 99 suchas with sodium borohydride. Amination of the ketoalkylethers 99 byreaction with ammonium acetate and sodium cyanoborohydride in thepresence of acetic acid generates the aminoalkylethers 100. Acetylationof the aminoethers 100 by acid chlorides or anhydrides in the presenceof base, such as trialkylamines, produces the amidoalkylethers 102.

[0406] Scheme XXII shows the preparation of ethers 105 and amides 107antiinflammatory agents of the present invention. Esters 103 where R^(i)is alkyl, can be converted to the alcohols 104 by treatment with areducing agent, such as DIBAL-H. The ethers 105 are formed by reactingwith an aralkyl halide in the presence of base. Alternatively, theesters 103 can be hydrolyzed to the acids 106 with base such as LiOH.Amides 107 are formed from the acid 106 by treatment with thionylchloride to form the acid chlorides, followed by substitution witharalkylamines.

[0407] Scheme XXIII shows the preparation of the antiinflammatory esters109 and amides 110 of the present invention. Base treatment of ester108, such as with sodium hydride, followed by addition of an aralkylhalide or heteroaralkyl halide forms the ester 109. Formation of theamide 110 from the esters 109 occurs in a three step procedure.Treatment with base, such as lithium hydroxide, and thionyl chlorideyields the acid chloride. Addition of an amine yields the amide 110.

[0408] Scheme XXIV shows the preparation of the antiinflammatory ethersand thioethers 116 of the present invention. Ethyl bromoacetate is addedto a mixture of hydroxy ormercaptan-substituted-(tetrahydro-2H-pyran-4-yl)benzene 111 and base togive the acetate 112. The acid 113 is formed from acetate 112 such as bytreatment with ethanolic LiOH. Addition of bromoethanone 114 to the acid115 in a solvent such as dimethylformamide gives the benzoin ester 115.The benzoin ester 115 is heated with acetic acid and ammonium acetate togive the oxazole 116.

[0409] Scheme XXV shows the preparation of the antiinflammatory amides123 and amines 124 of the present invention. Protected amino acid 118and bromoethanone 117 is treated with base and 18-crown-6 to afford thebenzoin ester 119. This benzoin ester 119 is treated with acetic acidand ammonium acetate and heated to provide the protected2-(aminoalkyl)oxazole 120. The protected 2-(aminoalkyl)oxazole 120 isdeprotected, such as by hydrogenation with 10% Pd on carbon, to give the2-(aminoalkyl)oxazole 121. (Tetrahydro-2H-pyran-4-yl)phenoxyacetic acidderivative 122 is coupled with 2-(aminoalkyl)oxazole 121 such as withHOBt and EDC to afford amide 123. Reduction of amide 123 such as withLiAlH₄ provides the amine 124.

[0410] Scheme XXVI shows the preparation of the antiinflammatory etherderivatives 130 of the present invention. A solution of the appropriatehetero-substituted ester and base is added to a[tetrahydropyran-4-yl]-α-bromotoluene 125 to give the[tetrahydropyran-4-yl]phenylmethyl ester 126. The acid 127 is formedfrom ester 126 such as by treatment with ethanolic LiOH. Base is addedto acid 127 and 2-bromoethanone 128 is added to form the benzoin ester129. Acetic acid and ammonium acetate are added to benzoin ester 129 andheated to give the oxazole 130.

[0411] Scheme XXVII shows a method for preparing oxazoles 135. Asolution of aldehyde 131 and zinc iodide in an organic solvent such asdichloromethane is treated with trimethylsilylcyanide to give thetrimethylsilyl cyanohydrin. The trimethylsilyl cyanohydrin is added to asolution of R¹-magnesium bromide in diethyl ether while maintaining thetemperature between 25-35° C. to give the benzoin 132. The benzoin 132,pyridine, and acid chloride are reacted at room temperature to yield thebenzoin ester 133. Addition of ammonium acetate to the benzoin ester 133and heating yields the oxazole 135. Alternatively, the hydroxy-oxazoline134 is isolated. Dehydraton of the hydroxy-oxazoline 134 yields theoxazoles 135. By reversing the positions of R¹ and the phenyl group inbenzoin 132, oxazoles can be prepared where R¹ is at position 4.

[0412] Scheme XXVIII shows a method of preparingoxazolylbenzenesulfonamides 138 of the present invention. The oxazole136 is stirred with chlorosulfonic acid at about 5° C. to give thesulfonyl chlorides 137. The sulfonyl chloride 137 is reacted at about 5°C. with ammonium hydroxide to give the sulfonamides 138 of the currentinvention.

[0413] The following examples contain detailed descriptions of themethods of preparation of compounds of Formulas I-II. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. All compounds showed NMR spectra consistent withtheir assigned structures.

EXAMPLE 1

[0414]

4-[5-(4-Chlorophenyl)-3-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide

[0415] Step 1. Preparation ofMethyl-4-(4-chlorophenyl)-2,4-dioxobutanoate.

[0416] Dimethyl oxalate (15.27 g, 0.129 mol) and 4′-chloroacetophenone(20.0 g, 0.129 mol) were diluted with methanol (300 mL) and sodiummethoxide (25 wt % in methanol, 70 mL) was added in one portion. Thereaction was stirred at room temperature for 16 hours (the reactionbecame an insoluble mass during this time). The solid was mechanicallybroken up, hydrochloric acid (conc. 70 mL) was added, and the whitesuspension was stirred vigorously at room temperature for 1 hour. Thesuspension was cooled to 0° C. and held for 0.5 hour. The solid wasfiltered, and the filter cake was washed with cold water (100 mL). Upondrying, methyl-4-[4-(chloro)phenyl]-2,4-dioxobutanoate was obtained(16.94 g, 54.4%) as the enol: mp 108.5-110.5° C. ¹H NMR (CDCl₃/300 MHz)δ 7.94 (d, J=8.66 Hz, 2H), 7.48 (d, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95(s, 3H), 3.48 (s, 1H).

[0417] Step 2. Preparation of Methyl1-(4-aminosulfonylphenyl)-5-(4-chlorothenyl)-1H-pyrazole-3-carboxylate

[0418] Methyl-4-[4-(chloro)phenyl]-2,4-dioxobutanoate (5.0 g, 20.78mmol) was added to 4-sulfonamidylphenyl hydrazine hydrochloride (5.11 g,22.86 mmol) and methanol (50 mL). The reaction vessel was heated toreflux and held for 16 hours. A precipitate formed overnight. Thesuspension was cooled to 0° C., held for 0.5 hour, filtered and washedwith cold water to provide, after air drying, 7.91 g, 91% of crudepyrazole. Recrystallized 3.50 g from boiling ethanol to yield 3.14 g(90%) of pure methyl1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate:mp 227° C.; ¹H NMR (CDCl₃/300 MHz) δ 7.91 (d, J=8.86 Hz, 2H), 7.44 (d,J=8.86 Hz, 2H), 7.33 (d, J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 7.03(s, 1H), 3.96 (s, 3H). Mass Spectrum, MH+=392.

[0419] Anal. Calc'd for C₁₇H₁₄N₃O₄ClS: C, 52.11; H, 3.60; N, 10.72; Cl,9.05; S, 8.18. Found: C, 52.07; H, 3.57; N, 10.76; Cl, 9.11; S, 8.27.

[0420] Step 3. Preparation of1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid

[0421] Methyl1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate(1.0 g, 2.66 mmol) was added to tetrahydrofuran (20 mL). Aqueous sodiumhydroxide (2.5 N, 2.7 mL) and water (2.5 mL) were added, and thesuspension was heated to reflux and held for 16 hours. The solids alldissolved during this time. The reaction was cooled to room temperature,and hydrochloric acid solution (1 N, 11 mL) was added. The aqueoussuspension was extracted with methylene chloride (2×20 mL). The combinedorganic solution was dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to an oil. Trituration with 30 mL ofdichloromethane yielded, upon filtration and drying, 0.90 g (94%) of1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid as a white solid: mp 126-128° C.

[0422] Step 4. Preparation of4-[5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide.

[0423]4-[4-(Aminosulfonyl)phenyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid (3.8 g, 10 mmol) and tetrahydrofuran (100 mL) was stirred at roomtemperature during the dropwise addition of 1.0 M borane-tetrahydrofurancomplex (30 mL, 30 mmol). The mixture was allowed to reflux for 16hours. The solution was cooled and methanol was added dropwise until gasevolution ceased. Ethyl acetate (100 mL) was added and the solutionwashed with 1N hydrochloric acid, brine, sat. aq. sodium bicarbonatesolution, dried over magnesium sulfate, filtered and concentrated. Theresultant material was recrystallized from ethanol:water to yield4-[5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide(2.6 g, 71%) as a white solid: mp 192-194° C.; ¹H NMR (DMSO-d₆/300 MHz)δ 7.81 (d, j=8.7 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.42 (brs, 2H), 7.40(d, J=8.7 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 5.35 (t, J=8.0Hz, 1H), 4.50 (d, J=8.0 Hz, 2H). Anal. Calc'd for C₁₆H₁₄N₃SO₂Cl: C,52.82; H, 3.88; N, 11.55. Found: C, 52.91; H, 3.88; N, 11.50.

[0424] Step 5. Preparation of4-[5-(4-chlorophenyl)-3-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide.

[0425] A solution of (569 mg, 1.56 mmol) of4-[5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamidein 50 mL of dichloromethane was stirred at 25° C. as triethylamine (315mg, 3.12 mmol) was added dropwise, followed by the addition ofmethanesulfonyl chloride (215 mg, 1.88 mmol). The reaction was stirredfor 5 minutes, after which the organic solution was washed with 1N HCl,dried over sodium sulfate and concentrated in vacuo to give a yellow oil(500 mg), which was characterized as the expected mesylate by its NMRspectrum. This material was used without further purification.4-(5-Fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran (373 mg, 1.649mmol) and anhydrous potassium carbonate (228 mg, 1.649 mmol) weredissolved in 25 mL of anhydrous DMF. The solution was stirred at roomtemperature under a blanket of dry nitrogen for 20 minutes, then asolution of mesylate (500 mg, 1.374 mmol) in anhydrous DMF (15 mL) wasadded in one portion. The resulting solution was stirred at roomtemperature for 72 hours, then 1N HCl (30 mL) was added. After stirringan additional 0.5 hour, the system was extracted with ethyl acetate(2×40 mL). The combined organic solution was sequentially washed with 1N HCl (40 mL), saturated aqueous NaHCO₃ (2×40 mL), 50% saturated NaCl(2×40 mL), and brine (40 mL!), dried over MgSO₄ and filtered. Thesolvents were evaporated under reduced pressure to yield an oil. The oilwas purified by flash chromatography on silica gel eluting with 40%ethyl acetate in hexane to yield, upon concentration of the appropriatefractions (200 mg, 25%) of4-[5-(4-chlorophenyl)-3-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamideas a foam: Mass Spectrum: 572 (M+). High resolution mass spectrum Calc'dfor C₂₈H₂₇N₃O₄ClFS: 572.1422. Found: 572.1361. Anal. Calc'd. forC₂₈H₂₇N₃O₄ClFS.1.4 H₂O: C, 57.86; H, 5.17; N, 7.23; Cl, 6.10; S, 5.52.Found: C, 57.87; H, 4.92; N, 6.97; Cl, 6.10; S, 5.71.

EXAMPLE 2

[0426]

4-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]oxazole

[0427] Step 1. Esterification of1-(4-fluorophenyl)-2-hydroxy-2-[4-(methylsulfonylphenyl)ethanone

[0428] A solution containing (2.07 g, 6.71 mmol) of1-(4-fluorophenyl)-2-hydroxy-2-[4-(methylsulfonylphenyl)ethanone (U.S.Pat. No. 5,380,738, Jan. 10, 1995) in 100 mL of dichloromethane wasstirred at 25° C. as (2.71 mL, 33.55 mmol) of pyridine was added,followed by the addition of (1.27 mL, 8.05 mmol) of benzyloxyacetylchloride. The reaction was stirred at 25° C. for 48 hours, after whichthe resulting yellow solution was washed with 1N HCl, dried over Na₂SO₄and concentrated in vacuo. The oily yellow solid was purified via flashchromatography on a silica gel column using 20% ethyl acetate/hexane asthe eluent. This provided 2.22 g (73%) of a white foam, which wascharacterized as the benzoin ester on the basis of its NMR spectra:¹H-NMR (CDCl₃, 300 MHz) δ 3.03 (s, 3H), 4.23 (d, 1H, J=17.0 Hz), 4.33(d, 1H, J=17.0 Hz), 4.67 (s, 2H), 6.95 (s, 1H), 7.13 (t, 2H, J=8.5 Hz),7.35 (m, 5H), 7.66 (d, 2H, J=8.1 Hz) and 7.98 (m, 4H). ¹⁹F-NMR (CDCl₃,280 MHz) δ −102.5.

[0429] Step 2. Preparation of2-benzyloxymethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole.

[0430] A solution containing (2.22 g, 4.86 mmol) of the benzoin esterfrom Step 1 and (3.74 g, 48.6 mmol) of ammonium acetate in 100 mL ofacetic acid was heated to 80° C. for 2 hours. The reaction was cooled to25° C. and poured into water. The product was extracted into ethylacetate and the combined organic extracts were washed with an aqueoussolution of sodium bicarbonate. The solution was dried over sodiumsulfate and concentrated in vacuo to give a yellow oil. This crudematerial was purified by flash chromatography on a silica gel columnusing 25% ethyl acetate/hexane as the eluent to give2-benxyloxymethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole(1.92 g, 90%) as a clear oil: ¹H-NMR (CDCl₃, 300 MHz) δ 3.07 (s, 3H),4.70 (s, 2H), 4.72 (s, 2H), 7.11 (t, 2H, J=8.8 Hz), 7.22-7.40 (m, 5H),7.58 (m, 2H), 7.76 (d, 2H, J=8.8 Hz) and 7.91 (d, 2H, J=8.8 Hz). ¹⁹F-NMR(CDCl₃, 280 MHz) δ −111.88.

[0431] Step 3. Preparation of4-(4-fluorophenyl)-2-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]oxazole.

[0432] To a solution containing2-benxyloxymethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazolefrom Step 2 (5.0 g, 11.4 mmol) in 20 mL of 50% THF/methanol was added100 mg of 10% Pd on charcoal in a Fisher-Porter bottle. The reactionvessel was evacuated and charged with hydrogen at 50 psi for 24 hours.The Pd on carbon was removed by filtration through diatomaceous earthand the filtrate was concentrated in vacuo to give4-(4-fluorophenyl)-2-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]oxazole(3.8 g, 97%) as a white crystalline solid (recrystallized from 50% ethylacetate-isooctane): mp 156-157° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 3.07 (s,3H), 3.21 (bs, 1H), 4.81 (s, 2H), 7.10 (t, 2H, J=8.5 Hz), 7.56 (m, 2H),7.72 (d, 2H, J=8.8 Hz) and 7.90 (d, 2H, J=8.8 Hz); ¹⁹F-NMR (CDCl₃, 280MHz) δ −111.5. LRMS m/z 348 (M+H). HRMS Calc'd. for C₁₇H₁₄NO₄FS:348.0706. Found: 348.0681. Anal. Calc'd. for C₁₇H₁₄NO₄FS: C, 58.78; H,4.06; N, 4.03. Found: C, 58.67; H, 4.02; N, 4.01.

[0433] Step 4. Preparation of4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]oxazole.

[0434] A solution containing4-(4-fluorophenyl)-2-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]oxazolefrom Step 3 (169 mg, 0.487 mmol) in 20 mL of dichloromethane was stirredat 25° C. as triethylamine (136 μL, 0.974 mmol) was added dropwise,followed by the addition of mechanesulfonyl chloride (56 μL, 0.730mmol). The reaction was stirred for 5 minutes, after which the organicsolution was washed with 1N HCl, dried over sodium sulfate andconcentrated in vacuo to give a yellow oil which was characterized asthe expected mesylate by its NMR spectrum: ¹H-NMR (CDCl₃, 400 MHz) δ3.08 (s, 3H), 3.17 (s, 3H), 5.37 (s, 2H), 7.12 (t, 2H, J=8.8 Hz), 7.58(m, 2H), 7.78 (d, 2H, J=8.8 Hz) and 7.94 (d, 2H, J=8.8 Hz). Thismaterial was used without further purification. The mesylate wasdissolved in 20 mL of DMF and potassium carbonate (81 mg, 0.584 mmol)was added, followed by the addition of4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (122 mg, 0.584mmol). The reaction was stirred at 25° C. for 3 days and poured into 100mL of water. The aqueous solution was extracted with ethyl acetate andthe combined extracts were dried over sodium sulfate and concentrated invacuo to give a beige solid. This material was purified by flashchromatography on a silica gel column using 50% ethyl acetate/hexane asthe eluent to give4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]oxazole(185 mg, 71%) as a white crystalline solid: ¹H-NMR (CDCl₃, 300 MHz) δ1.90-2.05 (m, 4H), 2.97 (s, 3H), 3.08 (s, 3H), 3.81 (m, 4H), 5.25 (s,2H), 6.98-7.17 (m, 5H), 7.33 (t, 1H, J=7.7 Hz), 7.60 (m, 2H), 7.78 (d,2H, J=8.5 Hz) and 7.93 (d, 2H, J=8.5 Hz). ¹⁹F-NMR (CDCl₃, 280 MHz) δ−111.6. LRMS m/z 544 (M+Li). HRMS Calc'd. for C₂₉H₂₈NO₆FS: 544.1781(M+Li). Found: 544.1831 (M+Li).

EXAMPLE 3

[0435]

4-(4-Fluorophenyl)-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]-5-(4-(methylsulfonyl)phenyl)oxazole

[0436]4-(4-Fluorophenyl)-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]-5-(4-(methylsulfonyl)phenyl)oxazolewas prepared in a similar fashion from the reaction of the mesylate(Example 2, Step 4) and4-(3-fluoro-5-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran:¹H-NMR (CDCl₃, 300 MHz) δ 1.84-2.02 (m, 4H), 2.98 (s, 3H), 3.08 (s, 3H),3.81 (m, 4H), 5.23 (s, 2H), 6.76 (m, 2H), 6.92 (s, 1H), 7.13 (m, 2H),7.60 (m, 2H), 7.79 (d, 2H, J=8.5 Hz) and 7.93 (d, 2H, J=8.5 Hz). ¹⁹F-NMR(CDCl₃, 280 MHz) δ −110.8 and −111.7. Anal. Calc'd. for C₂₉H₂₇NO₆F₂: C,62.69; H, 4.90; N, 2.52. Found: C, 62.53; H, 4.96; N, 2.51.

EXAMPLE 4

[0437]

4-[2-[3-Fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide

[0438] Step 1. Preparation of 4,5-diphenyloxazolone.

[0439] Benzoin (31.8 g, 0.15 mol) and urethane (42.79 g, 0.45 mol) wereheated to reflux for 3.0 hours. The hot mixture was poured into water(150 mL). Acetone (150 mL) was added and heat was applied until themixture dissolved. The solution was cooled and filtered, producing awhite solid which was used in the next step without furtherpurification.

[0440] Step 2. Preparation of 2-chloro-4,5-diphenyloxazole.

[0441] 4,5-Diphenyloxazolone from Step 1 (30 g, 0.126 mol),triethylamine (12.8 g, 0.126 mol), and phosphorous oxychloride (96.6 g,0.63 mol) were stirred at reflux for 4.0 hours. The mixture wasconcentrated in vacuo, dissolved in ether (250 mL), washed with 1N HCl,brine, and water, dried over MgSO₄ and concentrated to a light yellowoil which was used in the next step without further purification orcharacterization.

[0442] Step 3. Preparation of4-[2-chloro-4-phenyl-5-oxazolyl]benzenesulfonamide.

[0443] Chlorosulfonic acid (20 mL) was cooled to 0° C. with stirring.2-Chloro-4,5-diphenyloxazole from Step 2 (1.53 g, 6 mmol) was added, andthe stirred solution was warmed to room temperature over 1.0 hour. Themixture was added dropwise to ice and dichloromethane (50 mL) withstirring. The resultant organic layer was washed once with water andadded to a 0° C. stirred solution of ammonium hydroxide (10 mL). Themixture was stirred for 1.0 hour and extracted with dichloromethane(3×50 mL). The combined organic layers were washed with 1 N HCl followedby brine and water, dried over MgSO₄ and concentrated. Recrystallizationfrom ethyl acetate/hexanes gave a white solid (1.5 g, 75%): mp 158-159°C. Anal. Calc'd. for C₁₅H₁₁N₂O₃SCl: C, 53.82; H, 3.31; N, 8.37. Found:C, 53.92; H, 3.32; N, 8.33.

[0444] Step 4. Preparation of4-[2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide

[0445] 4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide from Step 3(0.74 g, 2.2 mmol), N,N′-dimethylformamide (DMF) (20 mL), potassiumcarbonate (0.61 g, 4.4 mmol), and4-(3-fluoro-5-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran[prepared as described by G. C. Crawley, et al, J. Med. Chem., 35,2600-2609 (1992)] (0.75 g, 7.5 mmol) were stirred at room temperaturefor 16.0 hours. The solution was diluted with ethyl acetate (100 mL),washed with 1N HCl, brine and water, dried over MgSO₄ and concentrated.The residue was dissolved in ethyl acetate/hexanes (1:1) and filteredthrough silica. The eluant was concentrated and the residue wasrecrystallized from ethyl acetate/hexanes to afford4-[2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamideas a white solid (0.4 g, 35%): mp 159-161° C. ¹H NMR (CDCl₃) 300 MHz δ7.9 (d, J=8.7 Hz, 2H) 7.72 (d, J=8.7 Hz, 2H) 7.6 (m, 2H) 7.4 (m, 3H)7.24-7.30 (m, 2H) 7.0-7.1 (dt, J=9.5 Hz and J=1.8 Hz, 1H) 4.85 (bs, 2H)3.85 (dd, J=9.9 Hz and J=1.8 Hz, 4H) 3.05 (s, 3H) 2.0 (m, 4H). Anal.Calc'd. for C₂₇H₂₅N₂O₆SF: C, 61.82; H, 4.80; N, 5.34. Found: C, 61.77;H, 4.82; N, 4.31.

EXAMPLE 5

[0446]

4-[2-[3-(4-Methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide

[0447] 4-(2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide from Example4, Step 3, (0.6 g, 1.8 mmol), DMF (20 mL), potassium carbonate (0.5 g,3.6 mmol), and 4 (3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran(0.37 g, 1.8 mmol) [prepared as described by G. C. Crawley, et al, J.Med. Chem., 35, 2600-2609 (1992)] were stirred at room temperature for16.0 hours. The solution was diluted with ethyl acetate (100 mL), washedwith 1N HCl, brine and water, dried over MgSO₄ and concentrated. Theresidue was dissolved in ethyl acetate/hexanes (1:1) and filteredthrough silica. The eluant was concentrated and the residuerecrystallized from ethyl acetate/hexanes to give4-[2-(3-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy)-4-phenyl-5-oxazolyl]benzenesulfonamideas a white solid (0.4 g, 44%): mp 145-147° C. ¹H NMR (CDCl₃) 300 MHz δ7.88 (d, J=8.9 Hz, 2H) 7.70 (d, J=8.9 Hz, 2H) 7.6 (m, 2H) 7.36-7.5 (m,6H) 7.0-7.1 (dt, J=6.4 Hz and J=2.2 Hz, 1H) 4.85 (bs, 2H) 3.7 (m, 4H)3.05 (s, 3H) 2.0 (m, 4H). Anal. Calc'd. for C₂₇H₂₆N₂O₆S: C, 64.02; H,5.17; N, 5.53. Found: C, 63.94; H, 5.17; N, 5.55.

EXAMPLE 6

[0448]

4-[5-(4-Chlorophenyl)-3-(3-methoxyphenyl)thiomethyl-1Hpyrazol-1-yl]benzenesulfonamide

[0449] Step 1. Preparation of Methyl4-(4-chlorophenyl)-2,4-dioxobutanoate.

[0450] Dimethyl oxalate (15.27 g, 0.129 mol), and 4′-chloroacetophenone(20.0 g, 0.129 mol) were added to methanol (300 mL). Sodium methoxide(25 wt % in methanol, 70 mL) was added dropwise over about 0.5 hour. Thereaction was stirred at room temperature for 16 hours, whereupon thesodium salt of the butanoate precipitated from solution. The mixture wastreated with 70 mL of conc. HCl and the white suspension was stirredvigorously at room temperature for 1 hour. The suspension was cooled to0° C. and held for 0.5 hour. The solid was filtered, and the filter cakewas washed with cold water (100 mL). After drying in vacuo, methyl4-[4-(chloro)phenyl]-3-ketobutyrate was obtained (16.94 g, 54.4%) as theenol: ¹H NMR (CDCl₃/300 MHz) δ 7.94 (d, J=8.66 Hz, 2H), 7.48 (d, J=8.66Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H), 3.48 (s, 1H).

[0451] Step 2. Preparation of 4-[4-(aminosulfonyl)phenyl-5-(4chlorophenyl)-1H-pyrazole-3-carboxylic acid.

[0452] 4-Sulfonamidophenylhydrazine hydrochloride (1.45 g, 6.5 mmol) andmethyl-4-(4-chlorophenyl)-2,4-dioxobutanoate from Step 1 (1.2 g, 5.0mmol) were dissolved in 50 mL of methanol and heated to reflux for 20hours. After cooling to room temperature, the reaction mixture wasconcentrated in vacuo and the residue dissolved in ethyl acetate, washedwith water and brine, dried over anhydrous MgSO₄, filtered andre-concentrated to give a light brown solid. The crude solid wascrystallized from methanol and water to provide 1.6 g, 85% of purecompound. This material was dissolved in 150 mL of methanol and treatedwith 75 mL of 3N NaOH. The solution was heated to reflux for 3 hours,and concentrated in vacuo. The residue was acidified with conc. HCl andwas extracted into ethyl acetate. After removal of the ethyl acetate,the acid was isolated and dried to afford 1.4 g, (75%, mp 135° C.) thatwas used directly in the next step.

[0453] Step 3. Preparation of 4-[5-(4-chlorophenyl)-3-hydroxymethyl-1Hpyrazol-1-yl]benzenesulfonamide.

[0454] 4-[4-(Aminosulfonyl)phenyl-5-(4chlorophenyl)-1H-pyrazole-3-carboxylic acid from Step 2 (3.8 g, 10 mmol)and tetrahydrofuran (100 mL) were stirred at room temperature duringdropwise addition of 1.0 M borane-tetrahydrofuran complex (30 mL, 30mmol). The mixture was held at reflux for 16 hours. The mixture wascooled and methanol was added dropwise until gas evolution ceased. Ethylacetate (100 mL) was added and the mixture was washed with 1Nhydrochloric acid, brine, sat. aq. sodium bicarbonate solution, andwater, dried over magnesium sulfate, filtered and concentrated. Theresultant alcohol was recrystallized from ethanol:water to yield a whitesolid (2.6 g, 71%): mp 192-194° C. ¹H NMR (DMSO-d₆/300 MHz) δ 7.81 (d,J=8, 7 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.42 (brs, 2H), 7.40 (d, J=8.7Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 5.35 (t, J=8.0 Hz, 1H),4.50 (d, J=8.0 Hz, 2H). Anal. Calc'd for C₁₆H₁₄N₃SO₂Cl: C, 52.82; C,52.91; H, 3.88; H, 3.88; N, 11.55; N, 11.50.

[0455] Step 4. Preparation of4-[5-(4-chlorophenyl)-3-(3-methoxyphenyl)thiomethyl-1H-pyrazol-1-yl]benzenesulfonamide.

[0456]4-[5-(4-Chlorophenyl)-3-hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamidefrom Step 3 (500 mg, 1.374 mmol) was dissolved in anhydrous THF (30 mL).Triethylamine (0.385 mL, 2.749 mmol) and methanesulfonyl chloride (0.16mL, 2.062 mmol) were added sequentially, and the cloudy suspension wasstirred at room temperature for 0.5 hour. The reaction was diluted withethyl acetate (35 mL) and washed with aqueous HCl (1N, 50 mL). Theorganic solution was dried over anhydrous MgSO₄ and filtered, then thesolvent was evaporated under reduced pressure to yield a crude oil. Theoil was dissolved in anhydrous THF (10 mL). 3-Methoxythiophenol (0.205mL, 1.649 mmol) was dissolved in anhydrous THF. Sodium hydride (95%, 42mg, 1.649 mmol) was added, and the resulting frothy suspension wasstirred at room temperature for 20 minutes, forming a clear, colorlesssolution. The solution of the mesylate prepared above was added, thenthe reaction was warmed to 40° C. and held for 16 hours. The reactionwas cooled to room temperature then 1N HCl (30 mL) was added. Afterstirring an additional 0.5 hour, the system was extracted with ethylacetate (2×40 mL). The combined organic solution was sequentially washedwith 1 N HCl (40 mL), saturated aqueous NaHCO₃ (2×40 mL), 50% saturatedNaCl (2×40 mL), and brine (40 mL), then dried over anhydrous MgSO₄ andfiltered. The solvents were evaporated under reduced pressure to yieldan oil. The oil was purified by flash chromatography over silica geleluting with 40% ethyl acetate in hexane to yield4-[5-(4-chlorophenyl)-3-(3-methoxyphenyl)thiomethyl-1H-pyrazol-1-yl]benzenesulfonamide(273 mg, 41%) as a foam: Mass Spectrum: 486 (MH+). High resolution massspectrum Calc'd. for C₂₃H₂₀N₃O₃ClS₂: 486.0713. Found: 486.0757. Anal.Calc'd. for C₂₃H₂₀N₃O₃ClS₂: C, 56.84; H, 4.15; N, 8.65; Cl, 7.29; S,13.19. Found: C, 56.56; H, 4.22; N, 8.61; Cl, 7.41; S, 13.00.

EXAMPLE 7

[0457]

4-[5-(4-Chlorophenyl)-3-(3-methoxyphenyl)oxymethyl-1H-pyrazol-1-yl]benzenesulfonamide

[0458]4-[5-(4-Chlorophenyl)-3-(3-methoxyphenyl)oxymethyl-1H-pyrazol-1-yl]benzenesulfonamidewas prepared from4-[5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide(prepared in Example 6, step 3) in 39% yield by the method outlined inExample 1, Step 4: Mass Spectrum: 470 (MH+). High resolution massspectrum Calc'd. for C₂₃H₂₀N₃O₄ClS: 470.0979. Found: 470.0983. Anal.Calc'd. for C₂₃H₂₀N₃O₄ClS: C, 58.78; H, 4.29; N, 8.94; Cl, 7.54; S,6.82. Found: C, 58.85; H, 4.29; N, 8.90; Cl, 7.63; S, 6.93.

EXAMPLE 8

[0459]

4-[2-[[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide

[0460] Step 1. Preparation of2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenyl-ethanone.

[0461] Chlorosulphonic acid (100 mL) was cooled to 0° C. Deoxybenzoin(10 g, 51 mmol) was added, and the reaction was warmed from 0° C. toroom temperature over 4 h. The solution was carefully poured into icewater, filtered, and the aqueous layer was extracted with three 250 mLportions of CH₂Cl₂. The combined organic extracts were washed once withbrine (75 mL) and stirred over ice cold NH₄OH (125 mL) for 16 h. TheCH₂Cl₂ layer was separated and washed consecutively with 1N HCl (2×75mL), saturated aqueous NaHCO₃ (75 mL) and brine (75 mL), dried overNa₂SO₄, filtered, and concentrated. The crude material (4.23 g) wassuspended in acetic acid (75 mL) and a solution of HBr in acetic acid(33 V % HBr in HOAc, 25 mL), and bromine (0.79 mL, 15.4 mmol) was added.After 0.25 h at room temperature, the reaction was complete by TLC, andthe reaction was concentrated to remove the acetic acid. The residue wasdissolved in ethyl acetate (250 mL) and NaHSO₃ (10%, 250 mL). Theorganics were washed with saturated aqueous bicarbonate (75 mL) andbrine (75 mL), dried over Na₂SO₄, filtered, and concentrated yielding2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenyl-ethanone which was usedbelow without further purification.

[0462] Step 2. Preparation of4-[2-hydroxymethyl-4-phenyloxazol-5-yl]benzenesulfonamide.

[0463] Glycolic acid monosodium salt (1.55 g, 15.8 mol) and2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenylethanone (Step 1) weresuspended in DMF (350 mL) and stirred at room temperature for 16 h. Thereaction was concentrated. The resulting residue was combined withammonium acetate (2.31 g, 30 mmol) and acetic acid (25 mL), and themixture was heated to reflux for 3 h. The reaction was concentrated todryness, and the residue was dissolved in ethyl acetate (250 mL), washedwith water, saturated aqueous bicarbonate and brine, dried, filtered,and concentrated. The crude material was purified by flash columnchromatography on silica gel, eluting with a gradient from 50% to 75%ethyl acetate in hexane, to yield 1.89 g (37%) of4-[2-hydroxymethyl-4-phenyloxazol-5-yl]benzenesulfonamide: ¹H NMR(acetone-d₆/300 MHz) δ 4.76 (m, 2H), 6.68 (s, 2H), 7.45 (m, 3H), 7.65(m, 2H), 7.77 (d, 2H), J=6.8 Hz), 7.94 (d, 2H, J=8.7 Hz).

[0464] Step 3. Preparation of4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide.

[0465] A solution of4-[2-hydroxymethyl-4-phenyloxazol-5-yl]benzenesulfonamide (Step 2) (1.0g, 3 mmol) and triethylamine (0.61 g, 6 mmol) was stirred intetrahydrofuran (100 mL) at 0° C. Lithium chloride (0.25 g, 6 mmol) wasadded, followed by the dropwise addition of methanesulfonyl chloride(0.38 g, 3.3 mmol). After stirring for 3 h from 0° C. to 25° C., ethylacetate (100 mL) was added, and the mixture was washed with 1Nhydrochloric acid, brine and water, dried over magnesium sulfate,filtered, and concentrated. The crude product was purified by flashcolumn chromatography on silica gel eluting with a 1:1 mixture of ethylacetate:hexanes. The appropriate fractions were concentrated to a clearoil which solidified upon standing to give4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide as a whitesolid which was used in the next step without further purification orcharacterization.

[0466] Step 3. Preparation of4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide.

[0467] A mixture of4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide (Step 3) (0.5g, 1.4 mmol), potassium carbonate (0.4 g, 2.8 mmol), dimethylformamide(20 mL), and3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol [preparedas described in J. Med Chem., 35, 2600-2609 (1992)] (0.3 g, 1.4 mmol)was stirred at room temperature, for 16 h. Water (20 mL) was added, andthe mixture was extracted with ethyl acetate (4×30 mL) The combinedorganic layers were washed with brine, dried over magnesium sulfate andconcentrated. The resulting crude product was purified by flash columnchromatography on silica gel eluting with 50% ethyl acetate in hexanesto give 0.3 g (40%) of4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-pyran-4-yl)phenoxy]methyl]-4-phenyl-oxazol-5-yl]benzenesulfonamideas a sticky white solid: m.p. 70-80° C. ¹H NMR (CDCl₃/300 MHz) δ 7.92(d, 2H, J=8.9 Hz), 7.77 (d, 2H, J=8.9 Hz), 7.62 (m, 2H), 7.43 (m, 3H),6.94 (s, 1H), 6.78 (m, 2H) 5.24 (s, 2H), 4.82 (bs, 2H), 3.82 (m, 4H),3.00 (s, 3H), 1.95 (m, 4H). Anal. calcd for C₂₈H₂₇FN₂O₆S: C, 62.44; H,5.05; N, 5.20. Found: C, 62.50; H, 5.11; N, 5.24.

EXAMPLE 9

[0468]

Methyl5-[4-(aminosulfonyl)phenyl]-α-[[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl]methyl]-4-phenyloxazole-2-acetate

[0469] Step 1. Preparation of2-[(4-chlorosulfonyl)phenyl]-1-phenylethanone.

[0470] Deoxybenzoin (10 g, 0.051 mol) was added in portions to neatchlorosulfonic acid (50 mL) at −78° C. The reaction mixture was stirredat −78° C. for 2 h, then warmed to room temperature and for 1.5 h. Thereaction mixture was cooled to −78° C. carefully poured onto crushedice. The resulting solid was collected by filtration, washed with water,and dried to give 10.3 g (68%) of the desired sulfonyl chloride as ayellow solid. This crude material was used for the next reaction withoutfurther purification: HRMS: calcd for C₁₄H₁₁O₃SCl 295.0196, found295.0205.

[0471] Step 2. Preparation of2-[(4-aminosulfonyl)phenyl]-1-phenylethanone.

[0472] A solution of the sulfonyl chloride from Step 1 (9 g, 0.03 mol)in tetrahydrofuran (100 mL) was slowly added to ammonium hydroxide (100mL) at 5° C. The reaction mixture was stirred for 1.5 h at 5° C. and for30 minutes at room temperature. The resulting solid was collected byfiltration, washed with excess water and hexane, then vacuum dried togive 3.47 g (41%) of the desired sulfonamide as a white solid: m.p.259-261.5° C. ¹H NMR (DMSO-d₆/300 MHz) δ 4.52 (s, 2H), 7.30 (s, 2H),7.43 (bd, 2H, J=8.26 Hz), 7.54 (dd, 2H, J=7.56 Hz), 7.65 (dd, 1H, J=7.35Hz), 7.75 (d, 2H, J=8.26 Hz), 8.04 (d, 2H, J=7.45 Hz). HRMS: calcd forC₁₄H₁₃NO₃S 276.0694, found 276.0709.

[0473] Step 3. Preparation of2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenyl-ethanone.

[0474] The sulfonamide from Step 2 (5.0 g, 0.018 mol) was suspended indichloroethane (50 mL), then a solution of 30% HBr in acetic acid (20mL), acetic acid (70 mL) and bromine (1 mL) was added at roomtemperature. The reaction mixture was stirred for 40 minutes at roomtemperature and was concentrated in vacuo. Water (200 mL) was added tothe resulting concentrated residue, and the mixture was extracted withethyl acetate (2×250 mL) The combined ethyl acetate extracts were washedwith 5% sodium bicarbonate (2×250 mL), and brine (2×250 mL), dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Methylene chloride (50 mL) was added to the concentrated residue and asolid precipitated. This solid was collected by filtration, washed withcold methylene chloride and air-dried to give 3.5 g (55%) of2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenylethanone as a yellow solid:m.p. 153.6-155° C. ¹H NMR (DMSO-d₆/300 MHz) δ 7.25 (s, 1H), 7.38 (s,2H), 7.54 (dd, 2H, J=7.55 Hz), 7.62-7.74 (m, 3H), 7.82 (d, 2H, J=8.46Hz), 8.07 (d, 2H, J=8.66 Hz). HRMS: calcd for C₁₄H₁₂NO₃SBr 353.9800,found 353.9824.

[0475] Step 4. Preparation of Benzyl Methyl2-[3-[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl]malonate.

[0476] A solution of benzyl methyl malonate (0.88 g, 4.22 mmol) in 3 mLof anhydrous DMA was added to a suspension of sodium hydride (0.11 g,4.45 mmol) in 2 mL of anhydrous DMA at 5° C., and the reaction mixturewas stirred for 40 min at 5° C. Then3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene [prepared asdescribed in U.S. Pat. No. 5,424,320] (1.21 g, 4.24 mmol) was dissolvedin 6 mL of anhydrous DMA and added to this solution. The reactionmixture was stirred for 2 h at 5° C., and for 18 h at room temperature.The reaction mixture was quenched with water (100 mL). The aqueoussolution was extracted with ethyl acetate (3×70 mL) The combined organicextracts were washed with brine (1×100 mL), dried over magnesiumsulfate, filtered and concentrated. The concentrated residue waspurified by flash column chromatography on silica gel, eluting with 20%ethyl acetate in hexane, to give 0.93 g (53%) of benzyl methyl2-[3-[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl]malonate as a clearoil: HRMS: calcd for C₂₄H₂₈O₆ 413.1964, found 413.1952.

[0477] Step 5. Preparation of Monomethyl2-[3-[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl]malonate

[0478] A solution of benzyl methyl2-[3-[(4-methoxy)tetrahydropyran-4-yl]phenyl-methyl]malonate (0.3 g,7.27 mmol) in 15 mL of ethyl acetate was combined with 10% palladium onactivated carbon (0.17 g). The reaction mixture was stirred under 40 psiof hydrogen gas for 18 h at room temperature. The reaction mixture wasfiltered through Celite® and washed with excess ethyl acetate. Thefiltrate was concentrated and dried under vacuum to give 0.2 g (85%) ofmonomethyl 2-[3-[(4-methoxy)tetrahydropyran-4-yl]phenyl-methyl]malonateas a clear oil: HRMS: calcd for C₁₇H₂₂O₆ 323.1495, found 323.1473.

[0479] Step 6. Preparation of Methyl5-[4-(aminosulfonyl)phenyl]-α-[[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl]methyl]-4-phenyloxazole-2-acetate.

[0480] Solid NaOH (87 mg, 2.17 mmol) was added to a solution of themonomethyl 2-(3-[(4-methoxy)tetrahydropyran-4-yl]phenyl-methyl]malonate(Step 5) (0.7 g, 2.17 mmol) in ethanol (10 mL) and water (2 mL), and themixture was stirred for 15 min at room temperature. The solvents wereremoved at reduced pressure. Several mL of absolute ethanol were addedto the resulting residue, which was concentrated again at reducedpressure. This procedure was repeated three times until a white solidformed, which was dried under vacuum. The resulting carboxylic acidsodium salt was suspended in 2 mL of anhydrous DMF. A solution of2-bromo-2-[(4-amino-sulfonyl)phenyl]-1-phenylethanone (Step 3) (0.77 g,2.17 mmol) in anhydrous DMF (3 mL) was added at room temperature to theDMF solution of the sodium carboxylate. The reaction mixture was stirredfor 18 h at room temperature, and the DMF was removed at reducedpressure. Ethyl acetate (150 mL) was added to the concentrated residue,and the mixture was filtered. The filtrate was concentrated and dried togive the desired crude α-acyloxy ketone. Acetic acid (5 mL) and ammoniumacetate (1.5 g, 19.2 mmol) were added to this concentrated residue, andthe mixture was heated at 100° C. for 3 h. The reaction mixture wascooled to room temperature, and the excess acetic acid was removed undervacuum. The resulting residue was partitioned between water (100 mL) andethyl acetate (200 mL). The organic layer was separated, washed withsaturated aqueous sodium bicarbonate (2×100 mL), saturated brine (1×100mL), dried over magnesium sulfate, filtered and concentrated. Theconcentrated residue was purified by flash column chromatography onsilica gel, eluting with 2:1 ethyl acetate in hexane, to give 0.24 g ofa white solid which was recrystallized from methanol and water to give0.13 g (19%) of methyl5-[4-(aminosulfonyl)phenyl]-α-[[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl]-methyl]-4-phenyloxazole-2-acetateas a white solid: m.p. 88.7-94.9° C. ¹H NMR (CDCl₃/300 MHz) δ 1.78-1.88(m, 4H), 2.84 (s, 3H), 3.47-3.53 (m, 4H), 3.65-3.77 (m, 5H), 4.28 (dd,1H, J=7.05 Hz), 5.00 (s, 2H), 7.16-7.32 (m, 4H), 7.36-7.40 (m, 3H),7.54-7.58 (m, 2H), 7.68 (d, 2H, J=8.70 Hz), 7.88 (d, 2H, J=8.70 Hz).HRMS: calcd for C₃₁H₃₂N₂O₇S 577.2008. Found 577.1961.

EXAMPLE 10

[0481]

N-[2-[5-[4-(Aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamide

[0482]

N-[2-[4-[4-(Aminosulfonyl)phenyl]-5-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamide

[0483] Step 1. Preparation of Ethyl3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2-H-pyran-4-yl)phenoxyaceate.

[0484] A mixture of ethyl bromoacetate (0.5 g, 3 mmol),3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example8, Step 4) (0.3 g, 1.3 mmol) and K₂CO₃ (0.11 g, 0.8 mmol) indimethylformamide (5.0 mL) was stirred at room temperature for 16 hunder an argon atmosphere. The reaction mixture was partitioned between5% citric acid (25 mL) and EtOAc (25 mL). The organic phase was washedwith water, dried (Na₂SO₄), filtered and concentrated. The resultingsyrup was purified by flash column chromatography on silica gel, elutingwith 25% EtOAc in hexane, to give 0.3 g (73%) of ethyl3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyacetate asa colorless viscous liquid: ¹H NMR (CDCl₃/300 MHz) δ 6.77 (d, 2H, J=10.5Hz), 6.52 (d, 1H, J=10.5 Hz), 4.61 (s, 2H), 4.28 (q, 2H, J=6.9 Hz), 3.82(m, 4H), 2.99 (s, 3H), 1.92 (m, 4H), 1.31 (t, 3H, J=6.9 Hz). FABMSm/z=313 (M+H). HRMS calcd for C₁₆H₂₂FO₅ 313.1451, found 313.1399.

[0485] Step 2. Preparation of3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyaceticacid.

[0486] A solution of ethyl3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyacetate(Step 1) (0.3 g, 1 mmol) in ethanolic LiOH (1M, 1.5 mL) was stirred atroom temperature for 2 h. The reaction mixture was diluted with 5%citric acid (10 mL) and extracted with ether (2×15 mL). The etherextracts were combined and washed with water (2×20 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure to give 0.26 g (95%)of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyaceticacid as a colorless viscous liquid: ¹H NMR (CDCl₃/300 MHz) δ 6.78 (d,2H, J=10.5 Hz), 6.50 (d, 1H, J=10.5 Hz), 4.68 (s, 2H), 3.82 (m, 4H),2.99 (s, 3H), 1.92 (m, 4H); FABMS m/z=284 (M+H). HRMS calcd forC₁₄H₁₇FO₅ 283.0982, found 283.0993.

[0487] Step 3. Preparation of4-[2-[2-(N-methyl-N-phenylmethoxycarbonylamino)-ethyl]-4-phenyl-oxazol-5-yl]benzenesulfonamideand4-[2-[2-(N-methyl-N-phenylmethoxycarbonylamino)ethyl]-5-phenyloxazol-4-yl]benzene-sulfonamide.

[0488] A mixture of N-phenylmethoxycarbonyl-N-methyl-β-alanine (1.7 g,7.2 mmol) and 2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenylethanone(Example 8, Step 1) (2.0 g, 5.65 mmol) in dimethylacetamide (5.00 mL)was treated with K₂CO₃ (0.54 g, 3.9 mmol) and 18-crown-6 (0.05 g) andstirred at room temperature for 16 h. After the removal of the solventin vacuo, the residue was partitioned between cold water (25 mL) andEtOAc (50 mL). The organic phase was washed with water (2×25 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Theresulting substance was purified by flash column chromatography onsilica gel, eluting with 30% EtOAc in hexane, to afford the desiredα-acyloxyketone (2.2 g) as an amorphous substance. This benzoin ester(2.1 g) was dissolved in glacial acetic acid (20 mL), ammonium acetate(1.8 g, 23.4 mmol) was added, and the resulting mixture was heated at90° C. under a nitrogen atmosphere for 2.5 h. After cooling and theremoval of the solvent in vacuo, the residue was partitioned betweenwater (50 mL) and EtOAc (75 mL). The organic phase was washed with water(2×25 mL) dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The resulting material was purified by flash columnchromatography on silica gel, eluting with 40% EtOAc in hexane, toprovide 1.15 g (57%) of4-[2-[2-(N-methyl-N-phenylmethoxycarbonyl-amino)ethyl]-4-phenyl-oxazol-5-yl]benzenesulfonamideand4-[2-[2-(N-methyl-N-phenylmethoxycarbonylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamideas a white amorphous material containing the two isomeric oxazoleproducts: ¹H NMR (CDCl₃/300 MHz) δ 7.85 (d, 2H, J=8.7 Hz), 7.67 (m, 2H),7.54 (m, 2H), 7.42 (m, 3H), 7.28 (m, 5H), 5.08 (d, 2H, J=9.0 Hz), 4.9(br, 2H), 3.8 (t, 2H, J=6.9 Hz), 3.17 (m, 2H), 2.99 & 2.94 (s, 3H:).FABMS m/z=492 (M+H). HRMS calcd for C₂₆H₂₅N₃O₅S 492.1593, found492.1581.

[0489] Step 4. Preparation of4-[2-[2-(N-methylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and4-[2-[2-(N-methylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamide.

[0490] A solution of4-[2-[2-(N-methyl-N-phenylmethoxycarbonylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamideand4-[2-[2-(N-methyl-N-phenyl-methoxycarbonylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamide(0.7 g, 1.4 mmol) from Step 3, in MeOH (15 mL) containing acetic acid(0.1 mL) was treated with 10% Pd on carbon (0.4 g) and stirred under anatmosphere of hydrogen at 50 psi at room temperature for 3 h. Thecatalyst was removed by filtration, the filtrate was concentrated underreduced pressure, and the resulting substance was purified byreverse-phase HPLC using a gradient of 5-70% CH₃CN in water to give 0.42g of4-[2-[2-(N-methylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and4-[2-[2-(N-methylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamidetrifluoroacetate salts as a white powder: ¹H NMR (CD₃OD/300 MHz) δ 7.88(d, 2H, J=8.7 Hz), 7.74 (d, 2H, J=8.7 Hz), 7.6 (m, 2H), 7.43 (m, 3H),3.55 (t, 2H, J=6.6 Hz), 3.36 (t, 2H, J=6.6 Hz), 2.82 (s, 3H); FABMSm/z=358 (M+H).

[0491] Step 5. Preparation ofN-[2-[5-[4-(aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamideandN-[2-[4-[4-(aminosulfonyl)phenyl]-5-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamide.

[0492] To a solution of3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyaceticacid (0.27 g, 0.95 mmol) from Step 2 in dimethylacetamide (2.00 mL) anddichloromethane (3.00 mL), was added HOBt (0.22 g, 1.45 mmol) and EDC(0.19 g, 1 mmol), and the resulting mixture was stirred at 0° C. for 1h. This reaction mixture was treated with a solution of the free aminesgenerated by the addition of N-methylmorpholine (0.1 mL) to a solutionof the4-[2-[2-(N-methylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and4-[2-[2-(N-methylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamidetrifluoroacetates (0.36 g, 0.8 mmol) from Step 4 in dimethylacetamide(1.0 mL) at 0° C. The resulting mixture was warmed to room temperaturein 16 h. The reaction mixture was diluted with dichloromethane (20 mL),and washed sequentially with 5% citric acid, (2×10 mL), saturated NaHCO₃(2×10 mL), water, dried (Na₂SO₄), and filtered. After the removal of thesolvent under reduced pressure, the residue was purified by flash columnchromatography on silica gel, eluting with 1% MeOH in EtOAc, to affordthe desired product as a white amorphous (0.25 g, 52%) substance. Thismaterial was further purified by reverse-phase HPLC using a gradient of5-90% CH₃CN. The appropriate fractions were combined-and freeze-dried toafford an isomeric mixture ofN-[2-[5-[4-(aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamideandN-[2-[4-[4-(amino-sulfonyl)phenyl]-5-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamideas a white powder: ¹H NMR (CD₃OD/300 MHz) δ 7.85 (m, 2H), 7.71 & 7.64(d, 2H, J=8.7 Hz), 7.54 (m, 1H), 7.4-7.3 (m, 4H), 6.82-6.48 (m, 3H),4.82 & 4.76 (s, 2H), 3.78 (m, 2H), 3.75 (m, 4H), 3.17 (m, 2H), 3.16 &3.07 (s, 3H), 2.96 & 2.89 (s, 3H), 1.92-1.83 (m, 4H). FABMS m/z=624(M+H). HRMS calcd for C₃₂H₃₅N₃O₇FS 624.2180, found 624.2177.

EXAMPLE 11

[0493]

4-[2-[[2-[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]ethyl]-N-methylaminoethyl]-4-phenyloxazol-5-yl]benzenesulfonamide

[0494]

4-[2-[[2-[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]ethyl]-N-methylaminoethyl]-5-phenyloxazol-4-yl]benzenesulfonamide

[0495] A solution ofN-[2-[5-[4-(aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamideandN-[2-[4-[4-(aminosulfonyl)phenyl]-5-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamide(Example 10) (0.1 g, 0.16 mmol) in dry THF (4.00 mL) was combined withLiAlH₄ (0.016 g, 0.4 mmol) and stirred at room temperature for 16 hunder argon. The reaction mixture was cooled, and cold EtOAc (15 mL) wasadded. After stirring for 15 min, 0.5 N NaOH (15 mL) was added and thereaction mixture was filtered through Celite®. The organic phase waswashed with cold 0.5 N NaOH (10 mL), water, dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The resulting material waspurified by reverse-phase HPLC using a gradient of 5-90% CH₃CN in water.The appropriate fractions were combined and freeze-dried to provide anisomeric mixture of4-[2-[[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-pyran-4-yl)phenoxy]ethyl]-N-methylaminoethyl]-4-phenyloxazol-5-yl]-benzenesulfonamideand4-[2-[[2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-pyran-4-yl)phenoxy]ethyl]-N-methylaminoethyl]-5-phenyloxazol-4-yl]benzenesulfonamideas trifluoroacetate salts: ¹H NMR (CD₃OD/300 MHz) δ 7.88 (d, 2H, J=8.7Hz), 7.71 (dd, 2H, J=8.7, 2.4 Hz), 7.57 (m, 2H), 7.42 (m, 3H), 6.83 (m,2H), 6.65 (m, 1H), 4.46 & 4.38 (t, 2H J=6.0 Hz), 3.79-3.62 (m, 8H), 3.51& 3.41 (t, 2H, J=6.6 Hz), 3.12, 2.96 & 2.93 (s, 6H), 1.88 (m, 4H). FABMSm/z=610 (M+H). HRMS calcd for C₃₂H₃₇N₃O₆FS 610.2387, found 610.2373.

EXAMPLE 12

[0496]

4-[2-[[4-[3-[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]-1-propynyl]phenyl]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide

[0497] Step 1. Preparation of4-[[2-(4-iodophenyl)methyl]-4-phenyloxazol-5-yl]benzenesulfonamide.

[0498] A mixture of 2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenylethanone(Example 8, Step 1) (2.0 g, 5.65 mmol) and 4-iodophenylacetic acid (1.8g, 6.9 mmol) in dimethylaceatamide (6.0 mL) was treated with potassiumcarbonate (0.57 g, 4.13 mmol) and 18-crown-6 (0.06 g) and stirred atroom temperature for 4 h. The reaction mixture was diluted with coldwater (50 mL) and extracted with ethyl acetate (3×30 mL). The combinedorganic phases were washed with water (2×25 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The resultingmaterial was purified by flash chromatography on silica gel, elutingwith 40% EtOAc in hexane, to give the desired α-acyloxy ketone as anamorphous substance, which was used in the next reaction without furtherpurification: ¹H NMR (CDCl₃/300 MHz) δ 7.86 (m, 4H), 7.63 (d, 2H, J=8.4Hz), 7.59 (m, 3H), 7.41 (t, 2H, J=7.8 Hz), 7.03 (d, 2H, J=8.4 Hz), 6.89(s, 1H), 4.82 (s, 2H), 3.73 (q, 2H, J=5.1 Hz). FABMS m/z=536 (M+H⁺).HRMS: calcd for C₂₂H₁₉NO₅SI 536.0029, found 536.0023. A mixture of thisα-acyloxy ketone (2.2 g, 4.1 mmol), and ammonium acetate (1.3 g, 16.9mmol) in acetic acid (15.0 mL) was heated at 100° C. under a nitrogenatmosphere for 2.5 h. The reaction mixture was concentrated in vacuo,and the residue was partitioned between water (50 mL) and EtOAc (50 mL).The organic phase was washed with water (2×30 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The resulting solidwas triturated with methanol, cooled and filtered to give 1.1 g (52%) of4-[[2-(4-iodophenyl)methyl]-4-phenyloxazol-5-yl]benzenesulfonamide as apale yellow powder: m.p. 198-201° C. ¹H NMR (CDCl₃/300 MHz) δ 7.86 (d,2H, J=8.7 Hz), 7.7 (dd, 4H), 7.59 (m, 2H), 7.41 (m, 3H), 7.15 (d, 2H,J=8.1 Hz), 4.81 (s, 2H), 4.16 (s, 2H); FABMS m/z=517 (M+H⁺); HRMS calcdfor C₂₂H₁₈N₂O₃S₁I₁ 517.0083, found 517.0063.

[0499] Step 2. Preparation of3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenylpropynylether.

[0500] A mixture of propargyl bromide (0.9 g, 7.6 mmol, 80% in toluene)and 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol(Example 8, Step 4) (0.5 g, 2.2 mmol) in dimethylacetamide (5 mL) wasstirred in the presence of K₂CO₃ (0.17 g, 1.2 mmol) and 18-crown-6 (0.02g) for 16 h at room temperature. After the removal of the solvent invacuo, the residue was partitioned between EtOAc (30 mL) and water (30mL). The organic phase was washed with water, dried (Na₂SO₄), filtered,and concentrated. The residue was purified by flash columnchromatography on silica gel, eluting with 25% EtOAc in hexane, to give0.35 g (64%) of3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenylpropynylether as a pale yellow viscous liquid, which solidified upon drying:m.p. 75-77° C. ¹H NMR (CDCl₃/300 MHz) δ 6.81 (d, 1H, J=1.5 Hz), 6.75 (m,1H), 6.62 (m 1H), 4.69 (d, 2H, J=2.4 Hz), 3.82 (m, 4H), 3.0 (s, 3H),2.55 (t, 1H, J=4.5 Hz), 2.1-1.8 (m, 4H). FABMS m/z=271 (M+Li). HRMScalcd for C₁₅H₁₈FO₃Li 271.1322, found 271.1317.

[0501] Step 3. Preparation of4-[2-[[4-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]-1-propynyl]phenyl]methyl]-4-phenyloxazol-5-yl]benzene-sulfonamide.

[0502] A solution of4-[[2-(4-iodophenyl)methyl]-4-phenyloxazol-5-yl]benzene-sulfonamide(Step 1) (0.5 g, 0.97 mmol) and3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenylpropynylether(Step 2) (0.28 g, 1.1 mmol) in dimethylformamide (2.00 mL)containing triethyl amine (0.16 mL, 1.14 mmol), was treated withPdCl₂(PPh₃)₂ (0.1 g), and CuI (0.02 g) and stirred at room temperaturefor 4 h, under an argon atmosphere. The reaction mixture was partitionedbetween 5% citric acid (20 mL) and EtOAc (50 mL). The organic phase waswashed with 5% citric acid (2×15 mL), water (2×15 mL), dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The resultingsubstance was purified by flash column chromatography on silica gel,eluting with 40% EtOAc in hexane, to afford 0.38 g (60%) of4-[2-[[4-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]-1-propynyl]phenyl]-methyl]-4-phenyloxazol-5-yl]benzenesulfonamideas a pale yellow amorphous material: m.p. 86-100° C. ¹H NMR (CDCl₃/300MHz) δ 7.85 (d, 2H, J=8.7 Hz), 7.65 (d, 2H, J=8.7 Hz), 7.55 (m, 1H),7.42-7.2 (m, 8H), 6.82 (br s, 1H), 6.75-6.6 (m, 2H), 4.91 (s, 2H), 4.86(s, 2H), 4.21 (s, 2H), 3.79 (m, 4H), 2.98 (s, 3H), 2.1-1.85 (m, 4H).FABMS m/z=653 (M+H). HRMS calcd for C₃₅H₃₄N₂O₆FS 653.2122, found653.2133.

EXAMPLE 13

[0503]

4-[2-[[4-[3-[3-Fluoro-5-(3,4,5,6-tetrahydro-4-hydroxypyran-4-yl)phenoxy]-1-propynyl]-phenyl]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide

[0504] Step 1. Preparation of3-fluoro-5-(4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenylpropynylether.

[0505] To a solution of3-fluoro-5-(4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)-phenol [preparedas described in J. Med Chem., 35, 2600-2609 (1992)] (0.8 g, 3.8 mmol) indimethylacetamide (2.00 mL), was added propargyl bromide (2.5 mL, 80%solution in toluene), K₂CO₃ (0.3 g, 2.2 mmol), and 18-crown-6 (0.03 g),and the resulting mixture was heated at 80° C. for 24 h under a nitrogenatmosphere. The reaction mixture was diluted with cold water (50 mL) andextracted with EtOAc (2×25 mL). The organic extracts were combined,washed with water (2×20 mL), dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The residual brown liquid was purified by flashcolumn chromatography on silica gel, eluting with 60% EtOAc in hexane,to afford 0.5 g (53%) of3-fluoro-5-(4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenylpropynylether, which crystallized from CH₂Cl₂/hexane as a light brown powder:m.p. 120-122° C.

[0506]¹H NMR (CDCl₃/300 MHz) δ 6.9 (d, H, J=1.5 Hz), 6.64 (d, 1H, J=9.9Hz), 6.84 (d, 1H, J=9.9 Hz), 4.69 (d, 2H, J=2.4 Hz), 3.88 (m, 4H), 2.55(t, 1H, J=2.4 Hz), 2.14 (m, 2H), 1.66 (m, 2H). FABMS m/z=251 (M+H). HRMScalcd for C₁₄H₁₆FO₃ 251.1083, found 251.1053.

[0507] Step 2. Preparation of4-[2-[[4-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxypyran-4-yl)phenoxy]-1-propynyl]phenyl]methyl]-4-phenyloxazol-5-yl]benzene-sulfonamide.

[0508] To a solution of4-[[2-(4-iodophenyl)methyl]-4-phenyloxazol-5-yl]benzenesulfonamide(Example 12, Step 1) (0.35 g, 0.68 mmol) and3-fluoro-5-(4-hydroxy-3,4,5,6-tetra-hydro-2H-pyran-4-yl)phenylpropynylether (Step 1) (0.185 g, 0.78 mmol) in dimethylformamide (2.0 mL)containing triethylamine (0.15 mL, 1.1 mmol), PdCl₂(PPh₃)₂ (0.1 g) andCuI (0.02 g) were added, and the resulting mixture was stirred at roomtemperature for 3 h, under an argon atmosphere. The reaction mixture waspartitioned between 5% citric acid (20 mL) and EtOAc (50 mL). Theorganic phase was washed with 5% citric acid (2×15 mL), water (2×15 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresulting substance was purified by flash column chromatography onsilica gel, eluting with 60% EtOAc in hexane, to afford 0.25 g (47%) of4-[2-[[4-[3-[3-fluoro-5-(3,4,5,6-tetrahydro-4-hydroxypyran-4-yl)-phenoxy]-1-propynyl]phenyl]methyl]-4-phenyloxazol-5-yl]benzenesulfonamideas a pale yellow amorphous material: ¹H NMR (CDCl₃/300 MHz) δ 7.85 (d,2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.58 (m, 2H), 7.44-7.33 (m, 7H),6.95 (br, 1H), 6.82 (d, 1H, J=10 Hz), 6.64 (d, 1H, J=10 Hz), 4.91 (s,2H), 4.83 (s, 2H), 4.21 (s, 2H), 3.88 (m, 4H), 2.15 (m, 2H), 1.6 (m,2H). FABMS m/z=639 (M+H) HRMS calcd for C₃₆H₃₂N₂FO₆S 639.1965, found639.1954.

EXAMPLE 14

[0509]

4-[2-[[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-(4-fluorophenyl)oxazol-5-yl]benzenesulfonamide

[0510] Step 1. Preparation of2-[(4-Aminosulfonyl)phenyl]-1-(p-fluorophenyl)-ethanone.

[0511] Neat 2-(phenyl)-1-(p-fluorophenyl)ethanone (6.10 g, 28.54 mmol)was cooled to −78° C. in a dry ice methanol bath. Chlorosulfonic acid(15.0 mL) was added, and the solution was warmed to room temperatureover 1 h. The solution was stirred for 2 h and poured directly into ice(500 mL in 1000 mL Erlenmeyer flask). The resulting heterogeneousaqueous solution was extracted with ethyl acetate (2×300 mL). The ethylacetate layers were combined, extracted with water (1×100 mL) and mixedwith ammonium hydroxide solution (50 mL) for 1 h. The ethyl acetate wascollected, extracted with 1N HCl (2×200 mL), brine (1×200 mL), and driedover sodium sulfate. The solvent was removed to a volume of 50 mL andcrystals formed. The crystals were kept at room temperature for 4 h andcollected by vacuum filtration to give 3.1 g (37%) of2-[(4-aminosulfonyl)phenyl]-1-(p-fluoro-phenyl)ethanone: m.p. 198-204°C. ¹H NMR (CD₃OD/300 MHz) δ 4.46 (s, 2H), 7.23 (t, 2H, J=8.8 Hz), 7.43(d, 2H, J=8.5 Hz), 7.85 (d, 2H, J=8.5 Hz), 8.10-8.20 (m, 2H). FABMSm/z=294 (M+H⁺). HRMS calcd for C₁₄H₁₃FNO₃S 294.0600. Found 294.0583.

[0512] Step 2. Preparation of2-[(4-aminosulfonyl)phenyl]-2-bromo-1-(p-fluoro-phenyl)ethanone.

[0513] To a solution of2-[(4-aminosulfonyl)phenyl]-1-(p-fluorophenyl)ethanone (Step 1) (2.93 g,10.00 mmol) in acetic acid (25 mL) at room temperature was added 33% HBrin acetic acid (5.0 mL), followed by bromine (1.59 g, 10.00 mmol), andthe solution was stirred at room temperature for 1 h. The acetic acidwas removed at reduced pressure, and the resulting yellow liquid waspoured into ethyl acetate (100 mL). This solution was washed withsaturated sodium bicarbonate (2×100 mL), followed by brine (100 mL). Theethyl acetate layer was dried over anhydrous sodium sulfate, filtered,and the solvent was removed at reduced pressure to give 3.21 g (86%) of2-[(4-aminosulfonyl)phenyl]-2-bromo-1-(p-fluorophenyl)ethanone as agummy foam: ¹H NMR (CDCl₃/300 MHz) δ 5.05 (bs, 2H), 6.30 (s, 1H), 7.16(t, 2H, J=8.6 Hz), 7.67 (d, 2H, J=8.5 Hz), 7.92 (d, 2H, J=8.5 Hz),8.02-8.07 (m, 2H). FABMS m/z=389 (M+NH₃ ⁺). HRMS calcd for C₁₄H₁₂BrFNO₃S371.9705. Found 371.9721.

[0514] Step 3. Preparation of4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-(4-fluorophenyl)oxazol-5-yl]benzenesulfonamide.

[0515] A mixture of2-[(4-aminosulfonyl)phenyl]-2-bromo-1-(p-fluorophenyl)-ethanone (Step 2)(513 mg, 1.37 mmol) and the sodium salt of3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyaceticacid (Example 10, Step 2) (419 mg, 1.37 mmol) were combined indimethylformamide (3.0 mL) and stirred at room temperature for 1 h. Thesolvent was removed at reduced pressure, and the residue taken up inethyl acetate (20 mL). This solution was washed with saturated aqueoussodium chloride (2×10 mL), saturated sodium bicarbonate (2×20 mL), andaqueous sodium chloride (2×10 mL). The ethyl acetate solution was driedover sodium sulfate, and the solvent was removed at reduced pressure.The resulting residue was purified by flash column chromatography onsilica gel to give 419 mg (62%) of the desired α-acyloxyketone as awhite foam: m.p. 78-81.° C.

[0516]¹H NMR (CDCl₃/300 MHz) δ 1.91-1.98 (m, 4H), 2.96 (s, 3H),3.80-3.83 (m, 4H), 4.83 (ab, 2H, J_(ab)=16.7 Hz, ΔV=18.4 Hz), 4.93 (bs,2H), 6.59 (dt, 1H, J=10.0 Hz, J=2.2 Hz), 6.98 (s, 1H), 7.13 (m, 2H),7.59 (d, 2H, J=8.5 Hz), 7.89-8.00 (m, 4H). FABMS m/z=582 (M+Li⁺). HRMScalcd for C₂₈H₂₈F₂NO₈S 576.1504. Found 576.1507. This benzoin ester (180mg, 0.31 mmol) and ammonium acetate (180 mg, 2.5 mmol) was heated atreflux in acetic acid (5 mL) for 30 min, and the solvent was removed atreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel to give 65 mg (37%) of4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-(4-fluoro-phenyl)oxazol-5-yl]benzenesulfonamideas a white foam: m.p. 70-72° C. ¹H NMR (CDCl₃/300 MHz) δ 1.85-2.01 (m,4H), 2.98 (s, 3H), 3.80-3.83 (m, 4H), 4.82 (bs, 2H), 5.22 (s, 2H),6.70-6.80 (m, 2H), 6.92 (m, 1H), 7.04-7.18 (m, 2H), 7.58-7.64 (m, 2H),7.74 (d, 2H, J=8.7 Hz), 9.92 (d, 2H, J=8.7 Hz). FABMS: m/z=563 (M+Li).HRMS calcd for C₂₈H₂₇F₂N₂O₆S 557.1558. Found 557.1538.

EXAMPLE 15

[0517]

4-[2-[4-[[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]phenylmethyl]-4-phenyloxazol-5-yl]benzenesulfonamide

[0518] Step 1. Preparation of methyl4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoate.

[0519] A mixture of3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example8, Step 4) (1.5 g, 6.6 mmol), methyl 4-(bromomethyl)benzoate (1.7 g, 7.4mmol), K₂CO₃ (0.6 g, 4.3 mmol), 18-crown-6 (0.05 g) and KI (0.05 g) indimethylacetamide (5.00 mL) was stirred at room temperature for 16 h,and at 80° C. for 2 h. The reaction mixture was poured into cold water(100 mL) and extracted with EtOAc (2×25 mL). The combined organicextracts were washed with water (2×25 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel, eluting with 20% EtOAc inhexane, to furnish 2.2 g (88%) of methyl4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoateas a white solid: m.p. 88-89° C. ¹H NMR (CDCl₃/300 Hz) δ 8.07 (d, 2H,J=7.8 Hz), 7.5 (d, 2H, J=7.8 Hz), 6.81 (s, 1H), 6.72 (d, 1H, J=9.9 Hz),6.6 (d, 1H, J=9.9 Hz), 5.12 (s, 2H), 3.93 (s, 3H), 3.82 (m, 4H), 2.97(s, 3H), 1.92 (m, 4H). FABMS m/z 375 (M+H).

[0520] Step 2. Preparation of4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoicacid.

[0521] A solution of methyl4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoate(Step 1) (1.9 g, 5.1 mmol) in THF (5.0 mL) was treated with methanolic1M LiOH (8.0 mL) and stirred at room temperature for 2 h. The reactionmixture was acidified with 5% citric acid and extracted with EtOAc (2×25mL). The organic extracts were combined and washed with water (2×25 mL),dried (Na₂SO₄), filtered, and concentrated to give the correspondingacid (1.7 g, 93%) as a white powder. Crystallization from EtOAc/hexaneprovided an analytically pure sample of4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoicacid: m.p. 184-186° C. ¹H NMR (CDCl₃/300 MHz) δ 8.14 (d, 2H, J=8.4 Hz),7.54 (d, 2H, J=8.4 Hz), 6.82 (s, 1H), 6.75 (m, 1H), 6.62 (m, 1H), 5.14(s, 2H), 3.83 (m, 4H), 2.98 (s, 3H), 1.93 (m 4H). FABMS m/z=360 (M⁺).HRMS calcd for C₂₀H₂₁FO₅ 360.1373, found 360.1372.

[0522] Step 3. Preparation of4-[2-[4-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]phenylmethyl]-4-phenyloxazol-5-yl]benzenesulfonamide.

[0523] A solution of4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoicacid (Step 2) (0.6 g, 1.67 mmol) and2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenyl-ethanone (0.5 g, 1.4 mmol)in dimethylacetamide (3.00 mL) was treated with K₂CO₃ (0.17 g, 1.23mmol) and 18-crown-6 (0.02 g), and the resulting mixture was stirred atroom temperature for 2.5 h. The reaction mixture was poured into coldwater (50 m-T) and extracted with EtOAc (3×25 mL). The organic extractswere combined and washed with water (2×25 mL), dried (Na₂SO₄), filteredand concentrated under reduced pressure to afford 0.9 g of the desiredbenzoin ester as an amorphous substance which was used in the next stepwithout further purification: FABMS m/z=634 (M+H). HRMS calcd forC₃₄H₃₃FNSO₈ 634.1911, found 634.1939. This benzoin ester (0.8 g, 1.3mmol) was dissolved in glacial acetic acid (8.0 mL), ammonium acetate(0.5 g, 6.5 mmol) was added, and the resulting mixture was heated at100° C. under a nitrogen atmosphere for 3 h. After the removal of thesolvent in vacuo, the residue was partitioned between water (50 mL) andEtOAc (30 mL). The organic phase was washed with water (2×25 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Theresulting material was purified by flash column chromatography on silicagel, eluting with 40% EtOAc in hexane, to provide 0.45 g (58%) of4-[2-[4-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]phenylmethyl]-4-phenyloxazol-5-yl]benzenesulfonamideas a white amorphous material: m.p. 93-99° C. ¹H NMR (CDCl₃/300 MHz) δ8.19 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.1 Hz), 7.82 (d, 2H, J=8.7 Hz),7.68 (m, 2H), 7.57 (d, 2H, J=8.1 Hz), 7.45 (m, 3H), 6.84 (s, 1H), 6.73(d, 1H, J=9.9 Hz), 6.64 (d, 1h, J=9.9 Hz), 5.14 (s, 2H), 4.84 (s, 2H),3.83 (m, 4H), 2.99 (s, 3H), 1.97 (m, 4H); FABMS m/z=615 (M+H). HRMScalcd for C₃₄H₃₂FN₂SO₆ 615.1965, found 615.1937.

EXAMPLE 16

[0524]

4-[5-[[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-3-phenylisoxazol-4-yl]benzenesulfonamide

[0525] A solution of4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (1.0 g, 3.2 mmol)and N, N, N′, N′-tetramethylethylenediamine (1.12 g, 9.6 mmol) intetrahydrofuran (100 mL) was cooled to −78° C. Butyllithium (6 mL, 1.6M, 9.6 mmol) was then added to this solution. After 30 min,hexachloroethane (2.27 g, 9.6 mmol) was added to the reaction mixture,the reaction mixture was warmed to −30° C., and then quenched withdilute hydrochloric acid. The reaction mixture was extracted with ethylacetate (100 mL), washed with brine, dried and concentrated to afford a1:1 mixture of the desired 5-chloromethyl isoxazole product and thestarting material as an inseparable mixture, which was carried to thenext stage without further purification. The crude 5-chloromethylisoxazole (0.25 g, 0.718 mmol) was added to a solution of3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example8, Step 4) (0.324 g) in dioxane (5 mL) and aqueous sodium hydroxide (1N,2.86 mL), and the reaction mixture was stirred for 3 days at roomtemperature. The reaction mixture was diluted with water (20 mL) andextracted with ethyl acetate (2×20 mL). The organic layers were combinedand washed with water and brine, dried, filtered, and concentrated. Theresulting residue was purified by flash column chromatography on silicagel, eluting with 1:2 ethyl acetate in hexane, to give 0.130 g (67%) of4-[5-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)-phenoxy]-methyl]-3-phenylisoxazol-4-yl]benzenesulfonamideas a crystalline solid: ¹H NMR (CDCl₃/300 MHz) δ 7.93 (d, 2H, J=8.5 Hz),7.42-7.36 (m, 7H), 6.78-6.54 (m, 3H), 5.15 (s, 2H), 3.79-3.82 (m, 4H),2.99 (s, 3H), 1.88-1.86 (m, 4H). FABMS m/z=545 (M+Li). HRMS calcd forC₂₈H₂₇N₂FO₆S 538.1652. Found 539.1652 (M+H).

EXAMPLE 17

[0526]

4-[2-[[[3-(3,4,5,6-Tetrahydro-4-methoxypyran-4-yl)phenylmethyl]oxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide

[0527] Step 1. Preparation of methyl3-[(4-methoxy)tetrahydropyran-4-yl]phenyl-methoxyacetate.

[0528] A solution of methyl glycolate (0.35 g, 3.9 mmol) in 5 mL ofanhydrous DMF was added to a suspension of sodium hydride (0.11 g, 4.6mmol) in 5 mL of anhydrous DMF at 5° C., and the reaction mixture wasstirred for 40 minutes at 5° C. A solution of3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene (1 g, 3.9 mmol) in 10mL of anhydrous DMF was added to the cold methyl glycolate solutionwhile maintaining the temperature at 5° C. The mixture was stirred for 2h at 5° C., then for 18 h at room temperature. The mixture was quenchedwith water (100 mL) and the aqueous solution was extracted with ethylacetate (2×100 mL). The combined organic extracts were washed withsaturated brine (1×100 mL), dried over magnesium sulfate, filtered andconcentrated. The concentrated residue was purified by flash columnchromatography on silica gel, eluting with 25% ethyl acetate in hexane,to give 0.57 g (50%) of methyl3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethoxyacetate as a clear oil:HRMS calcd for C₁₆H₂₂O₅ 295.1545. Found 295.1502.

[0529] Step 2. Preparation of3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethoxy-acetic acid.

[0530] A solution of methyl3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethoxy-acetate (Step 1) (0.5g, 1.7 mmol) and LiOH (0.18 g, 4.25 mmol) in 10% water and methanol (5mL) was stirred for 6 h at room temperature. The solvents were removedat reduced pressure, and the concentrated residue was partitionedbetween ethyl acetate (100 mL) and 1 N HCl (30 mL). The organic layerwas separated and washed with saturated brine (1×100 mL), dried overmagnesium sulfate, filtered and concentrated. The concentrated residuewas vacuum dried to give 0.46 g (97%) of3-[(4-methoxy)-tetrahydropyran-4-yl]phenyl-methoxyacetic acid as ayellow solid: HRMS calcd for C₁₅H₂₀O₅ 280.1311. Found 280.1304.

[0531] Step 3. Preparation of4-[2-[[[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenylmethyl]oxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide.

[0532] An aqueous solution of 2.5 N NaOH (1.2 mL, 2.7 mmol) was added to3-[(4-methoxy)tetrahydropyran-4-yl]phenylmethoxyacetic acid (0.76 g, 2.7mmol) in ethanol (10 mL), and the mixture was stirred for 15 min at roomtemperature. The solvents were removed at reduced pressure. Several mLof absolute ethanol were added to this concentrated residue, and themixture was again concentrated at reduced pressure. This procedure wasrepeated three times until a white solid formed, which was dried underhigh vacuum. The resulting carboxylic acid sodium salt was suspended in4 mL of anhydrous DMF. A solution of2-bromo-2-[(4-amino-sulfonyl)phenyl]-1-phenyl-ethanone (1.1 g, 2.7 mmol)in 4 mL of DMF was added at room temperature. The reaction mixture wasstirred for 18 h at room temperature, and the DMF was removed at reducedpressure. Ethyl acetate (100 mL) was added to this concentrated residue,and this mixture was filtered. The filtrate was concentrated and driedto give the desired crude α-acyloxy ketone. Acetic acid (5 mL) andammonium acetate (0.8 g, 10 mmol) were added to this concentratedresidue, and this mixture was heated at 100° C. for 3 h. The reactionmixture was cooled to room temperature, and the excess acetic acid wasremoved under vacuum. The resulting residue was partitioned betweenwater (100 mL) and ethyl acetate (100 mL). The organic layer wasseparated, washed with saturated aqueous sodium bicarbonate (2×100 mL),saturated brine (1×100 mL), dried over magnesium sulfate, filtered andconcentrated. The concentrated residue was purified by flash columnchromatography on silica gel, eluting with 20% to 45% ethyl acetate inhexane, to give 0.19 g (13%) of4-[2-[[[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenylmethyl]oxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamideas a white solid: m.p. 62.1-71.2° C. ¹H NMR (CDCl₃/300 MHz) δ 1.91-1.95(m, 4H), 2.94 (s, 3H), 3.75-3.88 (m, 4H), 4.73 (s, 2H), 4.74 (s, 2H),4.92 (s, 2H), 7.30-7.44 (m, 7H), 7.60-7.63 (m, 2H), 7.73-7.76 (m, 2H),7.89-7.92 (m, 2H). HRMS calcd for C₂₉H₃₀N₂O₆S 535.1903. Found 535.1865.

EXAMPLE 18

[0533]

4-[2-[[[3-(3,4,5,6-Tetrahydro-4-methoxypyran-4-yl)phenylmethyl]thio]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide

[0534] Step 1. Preparation of Methyl3-[(4-methoxy)-tetrahydropyran-4-yl]phenyl-methylthioacetate.

[0535] A solution of 3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene(1.0 g, 3.87 mmol) in 10 mL of anhydrous THF was cooled to 5° C. Asolution of methyl thioglycolate (0.41 g, 3.87 mmol) and DBU (0.59 g,3.87 mmol) in 10 mL of THF was added while maintaining the temperatureat 5° C. The reaction mixture was stirred for 2 h at room temperature.The reaction mixture was diluted with 250 mL of ethyl acetate, and theorganic layer was washed with 1 N HCl (2×100 mL), saturated sodiumbicarbonate (1×100 mL), brine (1×100 mL), dried over magnesium sulfate,filtered and concentrated. The concentrated residue was purified byflash column chromatography on silica gel, eluting with 40% ethylacetate in hexane, to give 0.87 g (72%) of methyl3-[(4-methoxy)-tetrahydropyran-4-yl]phenyl-methylthioacetate as a clearoil: ¹H NMR (CDCl₃/300 MHz) δ 1.94-2.09 (m, 4H), 2.97 (s, 3H), 3.08 (s,2H), 3.73 (s, 3H), 3.77-3.92 (m, 6H), 7.26-7.36 (m, 4H). HRMS calcd forC₁₆H₂₂O₄S 311.1317. Found 311.1271.

[0536] Step 2. Preparation of3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethyl-thioacetic acid.

[0537] A solution of methyl3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethyl-thioacetate (Step 1)(0.8 g, 2.58 mmol) and LiOH (0.27 g, 6.44 mmol) in 10% water andmethanol (10 mL) was stirred for 18 h at room temperature. The solventswere removed at reduced pressure, and the concentrated residue waspartitioned between ethyl acetate (200 mL) and 1 N HCl (100 mL). Theorganic layer was separated and washed with saturated brine (1×100 mL),dried over magnesium sulfate, filtered and concentrated. Theconcentrated residue was vacuum dried to give 0.75 g (98%) of3-[(4-methoxy)-tetrahydropyran-4-yl]phenyl-methylthioacetic acid as aclear oil: ¹H NMR (CDCl₃/300 MHz) δ 1.94-2.10 (m, 4H), 2.11 (s, 1H),2.98 (s, 3H), 3.10 (s, 2H), 3.81-3.91 (m, 6H), 7.28-7.38 (m, 4H). HRMScalcd for C₁₅H₂₀O₄S 297.1161. Found 297.1140.

[0538] Step 3. Preparation of4-[2-[[[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenylmethyl]thio]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide.

[0539] An aqueous solution of 2.5 N NaOH (0.97 mL, 2.43 mmol) was addedto a solution of3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethylthioacetic acid (Step 2)(0.72 g, 2.43 mmol) in ethanol (10 mL), and the mixture was stirred for15 min at room temperature. The solvents were removed at reducedpressure. Several mL of absolute ethanol were added to this concentratedresidue, and the mixture was again concentrated at reduced pressure.This procedure was repeated three times until a white solid formed,which was dried under high vacuum. The resulting carboxylic acid sodiumsalt was suspended in 10 mL of arhydrous DMF. A solution of2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenylethanone (Example 8, Step 1)(0.86 g, 2.43 mmol) in 8 mL of DMF was added at room temperature. Thereaction mixture was stirred for 1 h at room temperature, and the DMFwas removed at reduced pressure. Ethyl acetate (100 mL) was added tothis concentrated residue, and this mixture was filtered. The filtratewas concentrated and dried to give the desired crude α-acyloxy ketone.Acetic acid (5 mL) and ammonium acetate (0.8 g, 10 mmol) were added tothis concentrated residue, and the mixture was heated at 100° C. for 2h. The mixture was cooled to room temperature, and the excess aceticacid was removed under vacuum. The resulting residue was partitionedbetween water (100 mL) and ethyl acetate (250 mL). The organic layer wasseparated, washed with saturated aqueous sodium bicarbonate (2×100 mL),saturated brine (1×100 mL), dried over magnesium sulfate, filtered andconcentrated. The concentrated residue was purified by flash columnchromatography on silica gel, eluting with 40% ethyl acetate in hexane,to give 0.28 g (21%) or4-[2-[[[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenylmethyl]thio]methyl]-4-phenyl-oxazol-5-yl]benzenesulfonamideas a white solid: m.p. 77.2-81.7° C. ¹H NMR (CDCl₃/300 MHz) δ 1.80-1.94(m, 4H), 2.93 (s, 3H), 3.76-3.86 (m, 6H), 3.90 (s, 2H), 4.96 (s, 2H),7.24-7.32 (m, 3H), 7.41-7.44 (m, 4H), 7.61-7.64 (m, 2H), 7.71 (bd, 2H,J=8.40 Hz), 7.91 (bd, 2H, J=8.40 Hz). HRMS calcd for C₂₉H₃₀N₂O₅S₂551.1674. Found 551.1668.

EXAMPLE 19

[0540]

4-[2-[[[3-(3,4,5,6-Tetrahydro-4-methoxypyran-4-yl)phenylmethyl]thio]ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide

[0541] Step 1. Preparation of methyl3-[[(4-methoxy)tetrahydropyran-4-yl]phenyl-methylthio]propionate.

[0542] A solution of 3-[(4-methoxy)tetrahydropyran-4-yl)-α-bromotoluene(1.0 g, 3.87 mmol) in 10 mL of anhydrous THF was cooled to 5° C. Asolution of methyl 3-mercaptopropionate (0.46 g, 3.87 mmol) and DBU(0.59 g, 3.87 mmol) in 10 mL of THF was added while maintaining thetemperature at 5° C. The reaction mixture was stirred for 1 h at 5° C.and for 18 h at room temperature. The reaction mixture was diluted with200 mL of ethyl acetate, and this solution was washed with 1 N HCl(1×100 mL), saturated sodium bicarbonate (1×100 mL), brine (1×100 mL),dried over magnesium sulfate, filtered and concentrated. Theconcentrated residue was purified by flash column chromatography onsilica gel, eluting with 20% ethyl acetate in hexane, to give 0.94 g(75%) of methyl3-[[(4-methoxy)-tetrahydro-pyran-4-yl]phenylmethylthio]propionate as apink oil: ¹H NMR (CDCl₃/300 MHz) δ 1.93-2.09 (m, 4H), 2.54 (t, 2H, J=7.4Hz), 2.68 (t, 2H, J=7.5 Hz), 2.97 (s, 3H), 3.68 (s, 3H), 3.75 (s, 2H),3.80-3.92 (m, 4H), 7.23-7.36 (m, 4H). HRMS calcd for C₁₇H₂₄O₄S 325.1474.Found 325.1494.

[0543] Step 2. Preparation of3-[[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl-thio]propionic acid.

[0544] A solution of methyl3-[[(4-methoxy)tetrahydropyran-4-yl]phenyl-methyl-thio]propionate(Step 1) (0.91 g, 2.8 mmol) and LiOH (0.29 g, 7.01 mmol) in 10% waterand methanol (10 mL) was stirred for 18 h at room temperature. Thesolvents were removed at reduced pressure, and the concentrated residuewas partitioned between ethyl acetate (200 mL) and 1 N HCl (100 mL). Theorganic layer was separated and washed with saturated brine (1×100 mL),dried over magnesium sulfate, filtered and concentrated. Theconcentrated residue was vacuum dried to give 0.9 g of3-[[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl-thio]propionic acid asa clear, colorless oil: HRMS calcd for C₁₆H₂₂O₄S 310.1239, found310.1241.

[0545] Step 3. Preparation of4-[2-[2-[[5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl-methyl]thio]ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide.

[0546] An aqueous solution of 2.5 N NaOH (1.03 mL, 2.6 mmol) was addedto a solution of3-[[(4-methoxy)tetrahydropyran-4-yl]phenylmethylthio]propionic acid (0.8g, 2.6 mmol) in ethanol (10 mL), and the mixture was stirred for 15 minat room temperature. The solvents were removed at reduced pressure.Several mL of absolute ethanol were added to the concentrated residue,and the mixture was again concentrated at reduced pressure. Thisprocedure was repeated three times until a white solid formed, which wasdried under high vacuum. The resulting carboxylic acid sodium salt wassuspended in 10 mL of anhydrous DMF and combined with a solution of2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenylethanone (Example 8, Step 1)(0.91 g, 2.6 mmol) in 10 mL of DMF. The resulting mixture was stirredfor 18 h at room temperature, and the DMF was removed at reducedpressure. Ethyl acetate (100 mL) was added to this concentrated residue,and this mixture was filtered. The filtrate was concentrated and driedto give the desired crude α-acyloxy ketone. Acetic acid (5 mL) andammonium acetate (0.8 g, 10 mmol) were added to this concentratedresidue, and this mixture was heated at 100° C. for 2 h. The reactionmixture was cooled to room temperature, and the excess acetic acid wasremoved under vacuum. The resulting residue was partitioned betweenwater (100 mL) and ethyl acetate (250 mL). The organic layer wasseparated, washed with saturated aqueous sodium bicarbonate (2×100 mL),saturated brine (1×100 mL), dried over magnesium sulfate, filtered andconcentrated. The concentrated residue was purified by flash columnchromatography on silica gel, eluting with 40% to 45% ethyl acetate inhexane, to give 0.06 g (4%) of4-(2-[2-[[5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl-methyl]thio]ethyl]-4-phenyloxazol-5-yl]benzenesulfonamideas a white solid: m.p. 60.9-66.4° C. ¹H NMR (CDCl₃/300 MHz) δ 1.93-2.01(m, 4H), 2.91-2.95 (m, 5H), 3.12 (t, 2H, J=7.20 Hz), 3.76-3.87 (m, 6H),4.50 (s, 2H),7.29-7.43 (m, 7H), 7.58-7.61 (m, 2H), 7.69-7.72 (m, 2H),7.88-7.91 (m, 2H). HRMS calcd for C₃₀H₃₂N₂O₅S₂ 565.1831. Found 565.1852.

EXAMPLE 20

[0547]

4-[2-[3-(3,4,5,6-Tetrahydro-4-methoxypyran-4-yl)phenyl]methoxy]-4-phenyloxazol-5-yl3benzenesulfonamide

[0548] A solution of 3-[tetrahydro-(4-methoxy)pyran-4-yl]benzyl alcohol(prepared as described in U.S. Pat. No. 5,424,320) (0.07 g, 0.3 mmol) in2 mL of anhydrous DMA was added to a suspension of sodium hydride (7.2mg, 0.3 mmol) in 2 mL of anhydrous DMA at 5° C., and the reactionmixture was stirred for 20 minutes at 5° C. A solution of4-[(2-chloro)-4-phenyloxazol-5-yl]benzenesulfonamide in 2 mL ofanhydrous DMA was then added. The reaction mixture was stirred for 2 hat 5° C. and for 5 h at room temperature. The reaction mixture wasquenched with water (50 mL). The aqueous solution was extracted withethyl acetate (2×50 mL). The combined organic layers were washed withsaturated brine (1×100 mL), dried over magnesium sulfate, filtered andconcentrated. The concentrated residue was purified by flash columnchromatography on silica gel, eluting with 40% ethyl acetate in hexane,to give 0.1 g (64%) of4-[2-[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl]methoxy]-4-phenyloxazol-5-yl]-benzenesulfonamideas a white solid:

[0549]¹H NMR (CDCl₃/300 MHz) δ 1.95-2.06 (m, 4H), 2.98 (s, 3H),3.81-3.88 (m, 4H), 4.81 (s, 2H), 5.53 (s, 2H), 7.39-7.46 (m, 6H),7.55-7.67 (m, 5H), 7.84 (d, 2H, J=8.70 Hz). HRMS calcd for C₂₈H₂₈N₂O₆S521.1746. Found 521.1701.

EXAMPLE 21

[0550]

4-[2-[3-(3,4,5,6-Tetrahydro-4-methoxypyran-4-yl)phenyl]methylthio]-4-phenyloxazol-5-yl]benzenesulfonamide

[0551] To a solution of4-[(2-chloro)-4-phenyloxazol-5-yl]benzenesulfonamide (0.21 g, 0.63 mmol)in 2 mL of anhydrous THF at 5° C. was added a solution of3-[tetrahydro-(4-methoxy)pyran-4-yl]benzyl mercaptan (prepared asdescribed in U.S. Pat. No. 5,424,320) (0.15 g, 0.63 mmol) and DBU (95mg, 0.63 mmol) in 5 mL of THF while maintaining the temperature at 5° C.The reaction mixture was stirred for 1 h at 5° C. for 5 h at roomtemperature. The reaction mixture was diluted with 100 mL of ethylacetate and washed with 1 N HCl (1×100 mL), saturated aqueous NaHCO₃(1×100 mL), brine (1×100 mL), dried over magnesium sulfate, filtered andconcentrated. The concentrated residue was purified by flash columnchromatography on silica gel, eluting with 40% ethyl acetate in hexane,to give 0.19 g (56%) of4-[2-[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl]methylthio]-4-phenyloxazol-5-yl]benzenesulfonamideas a white solid: m.p. 74.7-78.5° C. ¹H NMR (CDCl₃/300 MHz) δ 1.85-1.97(m, 4H), 2.92 (s, 3H), 3.71-3.85 (m, 4H), 4.48 (s, 2H), 4.87 (s, 2H),7.29-7.47 (m, 7H), 7.60-7.69 (m, 4H), 7.86-7.90 (m, 2H). HRMS calcd forC₂₈H₂₈N₂O₅S₂ 537.1518. Found 537.1516.

EXAMPLE 22

[0552]

N-[2-[5-[4-(Aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethylamino]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]acetamide

[0553] Step 1. Preparation of4-[2-[2-(N-phenylmethoxycarbonylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide.

[0554] A mixture of N-phenylmethoxycarbonyl-β-alanine (1.5 g, 6.7 mmol)and 2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenylethanone (Example 8,Step 1) (2.0 g, 5.65 mmol) in dimethylacetamide (10.00 mL) was treatedwith K₂CO₃ (0.47 g, 3.4 mmol) and 18-crown-6 (0.033 g) and stirred atroom temperature for 16 h. After the removal of the solvent in vacuo,the residue was partitioned between cold water (25 mL) and EtOAc (50mL). The organic phase was washed with water (2×25 mL), dried (Na₂SO₄),and concentrated under reduced pressure. The resulting substance (2.8 g)was purified by flash column chromatography on silica gel, eluting with40% EtOAc in hexane, to afford the desired benzoin ester (2.0 g) as anamorphous substance which was used without further purification. Thebenzoin ester (1.6 g) was dissolved in glacial acetic acid (16 mL),treated with ammonium acetate (1.25 g, 16.2 mmol) and heated at 90° C.under a nitrogen atmosphere for 3 h. After the removal of the solvent invacuo, the residue was partitioned between water (50 mL) and EtOAc (50mL). The organic phase was washed with water (2×25 mL), dried (Na₂SO₄),and concentrated under reduced pressure. The resulting material waspurified by flash column chromatography on silica gel, eluting with 50%EtOAc in hexane, to provide 0.85 (55%) of4-[2-[2-(N-phenylmethoxycarbonyl-amino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamideas a white amorphous material: ¹H NMR (CDCl₃/300 MHz) δ 7.86 (d, 2H,J=8.4 Hz), 7.69 (d, 2H, J=8.4 Hz), 7.59 (m, 2H), 7.40 (m, 3H), 7.33 (m,5H), 5.45 (br, 1H), 5.10 (s, 2H), 4.91 (s, 2H), 3.74 (q, 2H, J=6.0 Hz),3.09 (t, 2H, J=6.0 Hz).; FABMS m/z=478 (M+H). HRMS calcd for C₂₅H₂₄N₃O₅S478.1437. Found 478.1412.

[0555] Step 2. Preparation of4-[2-(2-aminoethyl)-4-phenyloxazol-5-yl]benzenesulfonamide.

[0556] A solution of4-[2-[2-(N-phenylmethoxycarbonylamino)ethyl]-4-phenyl-oxazol-5-yl]benzenesulfonamide(Step 1) (0.75 g, 1.6 mmol) in MeOH (15 mL) containing acetic acid (0.1mL) was treated with 10% Pd on carbon (0.35 g) and stirred under anatmosphere of hydrogen at 50 psi at room temperature for 2.5 h. Thecatalyst was removed by filtration, and the filtrate was concentratedunder reduced pressure to afford a white powder which was purified byreverse-phase HPLC using a gradient of 10-90% CH₃CN in H₂O to afford0.55 g of 4-[2-(2-aminoethyl)-4-phenyloxazol-5-yl]benzenesulfonamide asits trifluoroacetate salt: ¹H NMR (CD₃OD/300 MHz) δ 7.91 (d, 2H, J=7.9Hz), 7.74 (m, 2H,), 7.63 (m, 2H), 7.44 (m, 3H), 3.49 (t, 2H, J=6.6 Hz),3.33 (t, 2H, J=6.6 Hz). FABMS m/z=344 (M+H). HRMS calcd for C₁₇H₁₈N₃O₅S344.1069. Found 344.1048.

[0557] Step 3. Preparation ofN-[2-[5-[4-(aminosulfonyl)phenyl]4-phenyloxazol-2-yl]ethylamino]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]-acetamide.

[0558] To a solution of3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)-phenoxyaceticacid (0.24 g, 0.85 mmol) (Example 8, Step 3) in dimethylacetamide (2.00mL) and dichloromethane (3.00 mL), HOBt (0.18 g, 1.18 mmol) and EDC(0.17 g, 0.89 mmol) were added, and the resulting mixture was stirred at0° C. for 1 h. This reaction mixture was treated with a solution of thefree amine generated by the addition of N-methylmorpholine (0.1 mL) to asolution of 4-[2-(2-aminoethyl)-4-phenyloxazol-5-yl]benzenesulfonamidetrifluoroacetate (0.3 g, 0.51 mmol) in dimethylacetamide (1.0 mL) at 0°C. The resulting mixture was warmed to room temperature in 16 h. Thereaction mixture was diluted with dichloromethane (20 mL), and washedsequentially with 5% citric acid, (2×10 mL), saturated NaHCO₃ (2×10 mL),water, and dried (Na₂SO₄). After the removal of the solvent underreduced pressure, the residue was purified by flash columnchromatography on silica gel, eluting with 80% EtOAc in hexane, toafford 0.31 g (52%) ofN-[2-[5-[4-(aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethylamino]-2-[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenoxy]acetamideas a white amorphous substance: ¹H NMR (CDCl₃/300 MHz) δ 7.88 (d, 2H,J=8.7 Hz), 7.72 (d, 2H, J=8.7 Hz), 7.58 (m, 3H), 7.43 (m, 3H), 6.74 (d,1H, J=9.6 Hz) 6.7 (m, 1H), 6.48 (m, 1H), 4.97 (s, 2H), 4.51 (s, 2H), 3.9(q, 2H, J=6.0 Hz), 3.79 (m, 4H), 3.13 (t, 2h, J=6.3 Hz), 2.95 (s, 3H),1.84 (m, 4H). FABMS m/z=610 (M+H). HRMS calcd for C₃₁H₃₃N₃O₇FS 610.2023.Found 610.2016.

Biological Evaluation

[0559] Rat Carrageenan Foot Pad Edema Test

[0560] The carrageenan foot edema test was performed with materials,reagents and procedures essentially as described by winter, et al.,(Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley ratswere selected in each group so that the average body weight was as closeas possible. Rats were fasted with free access to water for over sixteenhours prior to the test. The rats were dosed orally (1 mL) withcompounds suspended in vehicle containing 0.5% methylcellulose and0.025% surfactant, or with vehicle alone. One hour later a subplantarinjection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% salinewas administered and the volume of the injected foot was measured with adisplacement plethysmometer connected to a pressure transducer with adigital indicator. Three hours after the injection of the carrageenan,the volume of the foot was again measured. The average foot swelling ina group of drug-treated animals was compared with that of a group ofplacebo-treated animals and the percentage inhibition of edema wasdetermined (Otterness and Bliven, Laboratory Models for Testing NSAIDs,in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)).The % inhibition shows the % decrease from control paw volume determinedin this procedure and the data for selected compounds in this inventionare summarized in Table I. TABLE I RAT PAW EDEMA % Inhibition Example @10 mg/kg body weight 3 15

[0561] Evaluation of COX-1 and COX-2 Activity in vitro

[0562] The compounds of this invention exhibited inhibition in vitro ofCOX-2. The COX-2 inhibit on activity of the compounds or this inventionillustrated in the Examples was determined by the following methods.

[0563] a. Preparation of Recombinant COX Baculoviruses

[0564] Recombinant COX-1 and COX-2 were prepared as described by Gierseet al, [J. Biochem., 305, 479-84 (1995)]. A 2.0 kb fragment containingthe coding region of either human or murine COX-1 or human or murineCOX-2 was cloned into a BamHI site of the baculovirus transfer vectorpVL1393 (Invitrogen) to generate the baculovirus transfer vectors forCOX-1 and COX-2 in a manner similar to the method of D. R. O'Reilly etal (Baculovirus Expression Vectors: A Laboratory Manual (1992)).Recombinant baculoviruses were isolated by transfecting 4 μg ofbaculovirus transfer vector DNA into SF9 insect cells (2×10⁸) along with200 ng of linearized baculovirus plasmid DNA by the calcium phosphatemethod. See M. D. Summers and G. E. Smith, A Manual of Methods forBaculovirus Vectors and Insect Cell Culture Procedures, Texas Agric.Exp. Station Bull. 1555 (1987). Recombinant viruses were purified bythree rounds of plaque purification and high titer (10⁷-10⁸ pfu/ml)stocks of virus were prepared. For large scale production, SF9 insectcells were infected in 10 liter fermentors (0.5×10⁶/ml) with therecombinant baculovirus stock such that the multiplicity of infectionwas 0.1. After 72 hours the cells were centrifuged and the cell pellethomogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1%3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). Thehomogenate was centrifuged at 10,000×G for 30 minutes, and the resultantsupernatant was stored at −80° C. before being assayed for COX activity.

[0565] b. Assay for COX-1 and COX-2 Activity

[0566] COX activity was assayed as PGE₂ formed/μg protein/time using anELISA to detect the prostaglandin released. CHAPS-solubilized insectcell membranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (50 mM, pH 8.0) containing epinephrine,phenol, and heme with the addition of arachidonic acid (10 μM).Compounds were pre-incubated with the enzyme for 10-20 minutes prior tothe addition of arachidonic acid. Any reaction between the arachidonicacid and the enzyme was stopped after ten minutes at 37° C./roomtemperature by transferring 40 μl of reaction mix into 160 μl ELISAbuffer and 25 μM indomethacin. The PGE₂ formed was measured by standardELISA technology (Cayman Chemical). Results are shown in Table II.

Assay for 5-Lipoxygenase Activity

[0567] The 5-lipoxygenase (5-LO) activity of the compounds weredetermined by the calcium ionophore-induced Leukotriene B4 (LTB4)production in human whole blood. Venous blood was collected from healthyhuman donors using heparin as an anti-coagulant. Human blood samples(0.2 ml of a 1:4 dilution in RPMI 1640 medium) were incubated in 96-wellculture plates for 15 minutes at 37° C. with test compounds dissolved inethanol (EtOH; final concentration <1%), or vehicle. Typically 7concentrations of test compounds were examined in duplicate. A-23187[Sigma] was added to the blood to a final concentration of 20 μg/ml, andthe mixtures were incubated for 10 minutes at 37° C. The reaction wasstopped by placing the samples on ice. The samples were then centrifugedat 800×g at 4° C. for 10 minutes to pellet the cells, and thesupernatants were recovered for quantitation of LTB4 by -LISA (CaymanChemical Co.; sensitivity 3 pg/ml). IC₅₀'s were estimated from a fourparameter logistic model with two parameters fixed, the minimum (0%inhibition) and maximum (100% inhibition). The IC₅₀ value is theconcentration that produces 50% inhibition between the fixed values ofthe minimum and maximum. Data is reported as the mean IC₅₀ for eachcompound. Results are shown in Table II. TABLE II COX-2 COX-1 5-LOExample IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) 1 <0.1 38 0.15 2 0.2 >10 0.05 3<0.1 >100 0.02 4 <0.1 <0.1 14 5 <0.1 <0.1 17 6 <0.1 2.2 0.44 7 <0.1 3.80.65 8 <0.1 1.3 0.3 9 10 80 >10 12 <0.1 >100 >10 14 <0.1 5.0 0.2 16<0.1 >100 >10 17 0.5 >100 9.8 19 <0.1 2.3 >10 21 <0.1 2.6 >10 221.1 >100 >10

[0568] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of this combination therapyin association with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The active compounds andcomposition may, for example, be administered orally, intravascularly(IV), intraperitoneally, subcutaneously, intramuscularly (IM) ortopically.

[0569] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, hard or soft capsule, lozenges,dispensable powders, suspension or liquid. The pharmaceuticalcomposition is preferably made in the form of a dosage unit containing aparticular amount of the active ingredient. Examples of such dosageunits are tablets or capsules.

[0570] The active ingredient may also be administered by injection (IV,IM, subcutaneous or jet) as a composition wherein, for example, saline,dextrose, or water may be used as a suitable carrier. The pH of thecomposition may be adjusted, if necessary, with suitable acid, base, orbuffer. Suitable bulking, dispersing, wetting or suspending agents,including mannitol and PEG 400, may also be included in the composition.A suitable parenteral composition can also include a compound formulatedas a sterile solid substance, including lyophilized powder, in injectionvials. Aqueous solution can be added to dissolve the compound prior toinjection.

[0571] The amount of therapeutically active compounds that areadministered and the dosage regimen for treating a disease conditionwith the compounds and/or compositions of this invention depends on avariety of factors, including the age, weight, sex and medical conditionof he subject, the severity of the inflammation or inflammation relateddisorder, the route and frequency of administration, and the particularcompound employed, and thus may vary widely. The prodrug compositionsshould include similar dosages as for the parent compounds. Thepharmaceutical compositions may contain active ingredients in the rangeof about 0.1 to 1000 mg, preferably in the range of about 0.5 to 250 mgand most preferably between about 1 and 60 mg. A daily dose of about0.01 to 100 mg/kg body weight, preferably between about 0.05 and about20 mg/kg body weight and most preferably between about 0.1 to 10 mg/kgbody weight, may be appropriate. The daily dose can be administered inone to four doses per day.

[0572] In the case of skin conditions, it may be preferable to apply atopical preparation of compounds of this invention to the affected areatwo to four times a day.

[0573] For disorders of the eye or other external tissues, e.g., mouthand skin, the formulations are preferably applied as a topical gel,spray, ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include dimethylsulfoxide and relatedanalogs. The compounds of this invention can also be administered by atransdermal device. Preferably topical administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch.

[0574] The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waytogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

[0575] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties, since the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[0576] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients are dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The antiinflammatory active ingredients arepreferably present in such formulations in a concentration of 0.5 to20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.

[0577] For therapeutic purposes, the active compounds of thiscombination invention are ordinarily combined with one or more adjuvantsappropriate to the indicated route of administration. If administeredper os, the compounds may be admixed with lactose, sucrose, starchpowder, cellulose esters of alkanoic acids, cellulose alkyl esters,talc, stearic acid, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tablected or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

[0578] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations.

What is claimed is:
 1. A compound of Formula I

wherein A is a 5- or 6-member ring substituent selected from partiallyunsaturated or unsaturated heterocyclo and carbocyclic rings, wherein Ais optionally substituted with a radical selected from acyl, halo,alkyl, haloalkyl, cyano, nitro, carboxyl, alkoxy, oxo, aminocarbonyl,alkoxycarbonyl, carboxyalkyl, cyanoalkyl, and hydroxyalkyl; wherein Y isa radical selected from oxy, thio, sulfinyl, sulfonyl, alkyl, alkenyl,alkynyl, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl,haloalkyl, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkyloxyalkyl,hydroxyalkylthio, hydroxyalkylthioalkyl, oximinoalkoxy,oximinoalkoxyalkyl, (alkyl)oximinoalkoxy, (alkyl)oximinoalkoxyalkyl,oximinoalkylthio, oximinoalkylthioalkyl,(alkyl)oximinoalkylthio, (alkyl)oximinoalkylthioalkyl, carbonylalkyloxy,carbonylalkyloxyalkyl, carbonylalkylthio, carbonylalkylthioalkyl,heterocyclo, cycloalkenyl, aralkyl, heterocycloalkyl, acyl,alkylthioalkyl, alkyloxyalkyl, alkenylthio, alkynylthio, alkenyloxy,alkynyloxy, alkenylthioalkyl, alkynylthioalkyl, alkenyloxyalkyl,alkynyloxyalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,alkylarylalkynyloxy, alkylarylalkenyloxy, alkylarylalkynylthio,alkylarylalkenylthio, haloalkylcarbonyl, alkoxyalkyl,alkylaminocarbonylalkyl, heteroaralkoxyalkyl, heteroaryloxyalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, heteroaralkoxy,heteroaralkylthio, heteroaryloxy, heteroarylthio, arylthioalkyl,aryloxyalkyl, haloaryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonylcyanoalkenyl,aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl,N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloaminocarbonyl,carboxyalkylaminocarbonyl, alkylcarbonylalkyl,aralkoxycarbonylalkylaminocarbonyl, haloaralkyl, carboxyhaloalkyl,alkoxycarbonylhaloalkyl, aminocarbonylhaloalkyl,alkylaminocarbonylhaloalkyl, N-alkylamino, N,N-dialkylamino,N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,N-alkyl-N-arylamino, aminoalkyl, N-alkylaminoalkyl,N,N-dialkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aminoalkoxy,aminoalkoxyalkyl, aminoalkylthio, aminoalkylthioalkyl, cycloalkyloxy,cycloalkylalkyloxy, cycloalkylthio, cycloalkylalkylthio, aryloxy,aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl,N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl,

wherein Ar is selected from aryl and heteroaryl, wherein Ar isoptionally substituted with one or two substituents selected from halo,hydroxyl, mercapto, amino, nitro, cyano, carbamoyl, alkyl, alkenyloxy,alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,dialkylamino, haloalkyl, alkoxycarbonyl, N-alkylcarbamoyl,N,N-dialkylcarbamoyl, alkanoylamino, cyanoalkoxy, carbamoylalkoxy,alkoxycarbonylalkoxy and

wherein R¹ is one or more substituents selected from heterocyclo,cycloalkyl, cycloalkenyl and aryl, wherein R¹ is optionally substitutedat a substitutable position with one or more radicals selected fromalkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; wherein R² isselected from alkyl and amino; wherein R³ and R⁴ together form a groupof the formula -B-X-B¹ which together with the carbon atom to which Band B¹ are attached, defines a ring having 6 ring atoms, wherein B andB¹, which may be the same or different, each is alkylene and X is oxy,and which ring may bear one, two or three substituents, which may be thesame or different, selected from hydroxyl, alkyl, alkoxy, alkenyloxy andalkynyloxy; wherein R⁵ is selected from hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, carboxyl, aminocarbonyl,alkylaminocarbonyl, alkoxycarbonyl, acyl, and cyano; wherein R⁶ isselected from hydrido, alkyl, aryl and aralkyl; wherein R⁷ is selectedfrom alkyl, alkoxy, alkenyl and alkynyl; wherein R⁸ is oximinooptionally substituted with alkyl; and wherein n is 0 or 1; provided Aris substituted with

 when A is oxazolyl; or a pharmaceutically-acceptable salt thereof. 2.Compound of claim 1 wherein A is a radical selected from thienyl,oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl,triazolyl, isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl,wherein A is optionally substituted with a radical selected from acyl,halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, loweralkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lowercyanoalkyl, and lower hydroxyalkyl; wherein Y is a radical selected fromoxy, thio, sulfinyl, sulfonyl, lower alkyl, lower alkenyl, loweralkynyl, lower alkyloxy, lower hydroxyalkyl, lower hydroxyalkyloxy,lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, loweroximinoalkoxyalkyl, lower (alkyl)oximinoalkoxy, lower(alkyl)oximinoalkoxyalkyl, lower carbony-alkyloxy, lowercarbonylalkyloxyalkyl, lower hydroxyalkylthio, lowerhydroxyalkylthioalkyl, lower oximinoalkylthio, loweroximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower(alkyl)oximinoalkylthioalkyl, lower carbonylalkylthio, lowercarbonylalkylthioalkyl, lower alkylthio, lower alkylcarbonyl, lowercycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, lowercycloalkenyl, lower aralkyl, lower heterocycloalkyl, acyl, loweralkylthioalkyl, lower alkyloxyalkyl, lower alkenylthio, loweralkynylthio, lower alkenyloxy, lower alkynyloxy, lower alkenylthioalkyl,lower alkynylthioalkyl, lower alkenyloxyalkyl, lower alkynyloxyalkyl,phenylcarbonyl, lower aralkylcarbonyl, lower aralkenyl, loweralkylarylalkynyloxy, lower alkylarylalkenyloxy, loweralkylarylalkynylthio, lower alkylarylalkenylthio, lowerhaloalkylcarbonyl, lower alkylaminocarbonylalkyl, lowerheteroaralkoxyalkyl, lower heteroaryloxyalkyl, lowerheteroarylthioalkyl, lower heteroaralkylthioalkyl, lower heteroaralkoxy,lower heteroaralkylthio, lower heteroaryloxy, lower heteroarylthio,lower arylthioalkyl, lower aryloxyalkyl, lower aralkylthioalkyl, loweraralkoxyalkyl, lower alkoxyaralkoxyalkyl, lower alkoxycarbonylalkyl,lower alkoxycarbonylcyanoalkenyl, lower aminocarbonylalkyl, lowerN-alkylaminocarbonyl, N-phenylaminocarbonyl, lowerN,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lowercycloalkylaminocarbonyl, lower heterocycloaminocarbonyl, lowercarboxyalkylaminocarbonyl, lower alkylcarbonylalkyl, loweraralkoxycarbonylalkylaminocarbonyl, lower haloaralkyl, lowercarboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, loweraminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lowerN-alkylamino, lower N,N-dialkylamino, N-phenylamino, lowerN-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino,lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl,lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lowerN-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, loweraminoalkoxy, lower aminoalkoxyalkyl, lower aminoalkylthio, loweraminoalkylthioalkyl, lower cycloalkyloxy, lower cycloalkylalkyloxy,lower cycloalkylthio, lower cycloalkylalkylthio, phenyloxy, loweraralkoxy, phenylthio, lower aralkylthio, lower alkylsulfinyl, loweralkylsulfonyl, aminosulfonyl, lower N-alkylaminosulfonyl, lowerN-arylaminosulfonyl, lower arylsulfonyl, lower N,N-dialkylaminosulfonyl,lower N-alkyl-N-arylaminosulfonyl,

wherein Ar is selected from aryl selected from phenyl, biphenyl andnaphthyl, and 5- and 6-membered heteroaryl, wherein Ar is optionallysubstituted with one or two substituents selected from halo, hydroxyl,mercapto, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy,lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,lower alkylamino, lower dialkylamino, lower haloalkyl, loweralkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl,lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, loweralkoxycarbonylalkoxy and

wherein R¹ is at least one substituent selected from 5- and 6-memberedheterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected fromphenyl, biphenyl and naphthyl, where R¹ is optionally substituted at asubstitutable position with one or more radicals selected from loweralkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl,lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, loweralkoxy and lower alkylthio; wherein R² is selected from lower alkyl andamino; wherein R³ and R⁴ together form a group of the formula -B-X-B¹which together with the carbon atom to which B and B¹ are attached,defines a ring having 6 ring atoms, wherein B and B¹, which may be thesame or different, each is alkylene and X is oxy, and which ring maybear one, two or three substituents, which may be the same or different,selected from hydroxyl, lower alkyl, lower alkoxy, lower alkenyloxy andlower alkynyloxy; wherein R⁵ is selected from hydroxyl, lower alkoxy,lower alkylcarbonyloxy, phenylcarbonyloxy, carboxyl, aminocarbonyl,lower alkylaminocarbonyl, lower alkoxycarbonyl, lower acyl, and cyano;wherein R⁶ is selected from hydrido, lower alkyl, phenyl and loweraralkyl; wherein R⁷ is selected from lower alkyl, lower alkoxy, loweralkenyl and lower alkynyl; wherein R⁸ is oximino optionally substitutedwith alkyl; and wherein n is 0 or 1; or a pharmaceutically-acceptablesalt thereof.
 3. Compound of claim 2 wherein A is a radical selectedfrom thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl,isothiazolyl, triazolyl, isoxazolyl, pyrazolyl, cyclopentenyl, phenyl,and pyridyl, wherein A is optionally substituted with a radical selectedfrom acyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro,carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lowercarboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; wherein Y is aradical selected from oxy, thio, sulfinyl, sulfonyl, lower alkyl, loweralkenyl, lower alkynyl, lower alkyloxy, lower hydroxyalkyl, lowerhydroxyalkyloxy, lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, loweroximinoalkoxyalkyl, lower (alkyl)oximinoalkoxy, lower(alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, lowercarbonylalkyloxyalkyl, lower hydroxyalkylthio, lowerhydroxyalkylthioalkyl, lower oximinoalkalkylthio, loweroximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower(alkyl)oximinoalkylthioalkyl, lower carbonylalkylthio, lowercarbonylalkylthioalkyl, lower alkylthio, lower alkylcarbonyl, lowercycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, lowercycloalkenyl, lower aralkyl, lower heterocycloalkyl, acyl, loweralkylthioalkyl, lower alkyloxyalkyl, lower alkenylthio, loweralkynylthio, lower alkenyloxy, lower alkynyloxy, lower alkenylthioalkyl,lower alkynylthioalkyl, lower alkenyloxyalkyl, lower alkynyloxyalkyl,phenylcarbonyl, lower aralkylcarbonyl, lower aralkenyl, loweralkylarylalkynyloxy, lower alkylarylalkynylthio, lowerhaloalkylcarbonyl, lower alkylaminocarbonylalkyl, lower arylthioalkyl,lower aryloxyalkyl, lower aralkylthioalkyl, lower aralkoxyalkyl, loweralkoxycarbonylalkyl, lower aminocarbonylalkyl, lowerN-alkylaminocarbonyl, N-phenylaminocarbonyl, lower alkylcarbonylalkyl,lower N-alkylamino, N-phenylamino, lower N-aralkylamino, loweraminoalkyl, lower N-alkylaminoalkyl, lower N-arylaminoalkyl, lowerN-aralkylaminoalkyl, lower aminoalkoxy, lower aminoalkoxyalkyl, loweraminoalkylthio, lower aminoalkylthioalkyl, lower cycloalkyloxy, lowercycloalkylalkyloxy, lower cycloalkylthio, lower cycloalkylalkylthio,phenyloxy, lower aralkoxy, phenylthio, lower aralkylthio, loweralkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lowerN-alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, oximino,

wherein Ar is selected from aryl selected from phenyl, biphenyl,naphthyl, and 5- and 6-membered heteroaryl, wherein Ar is optionallysubstituted with one or two substituents selected from halo, hydroxyl,mercapto, amino, nitro, cyano, lower alkyl, lower alkoxy, and

wherein R¹ is at least one substituent selected from 5- and 6-memberedheteroaryl, and aryl selected from phenyl, biphenyl and naphthyl, whereR¹ is optionally substituted at a substitutable position with one ormore radicals selected from lower alkyl, lower haloalkyl, cyano,carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lowerhaloalkoxy, amino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo,lower alkoxy and lower alkylthio; wherein R² is selected from loweralkyl and amino; wherein R³ and R⁴ together form a tetrahydropyran ringand which ring may bear one, two or three substituents, which may be thesame or different, selected from hydroxyl, lower alkyl, and loweralkoxy; wherein R⁵ is selected from hydroxyl and lower alkoxy; whereinR⁶ is selected from hydrido, lower alkyl, phenyl and lower aralkyl; andwherein R⁷ is selected from lower alkyl, lower alkoxy, lower alkenyl andlower alkynyl; or a pharmaceutically-acceptable salt thereof. 4.Compound of claim 3 wherein A is a radical selected from thienyl,oxazolyl, furyl, pyrrolyl, thiazolyl, triazolyl, imidazolyl, isoxazolyl,pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A is optionallysubstituted with a radical selected from acyl, halo, lower alkyl, lowerhaloalkyl, oxo, cyano, carboxyl, lower alkoxy, aminocarbonyl, loweralkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lowerhydroxyalkyl; wherein Y is a radical selected from oxy, thio, sulfinyl,sulfonyl, lower alkyl, lower alkynyl, lower alkenyl, aryl, lowercycloalkyl, 5- or 6-membered heterocyclo, aralkyl, lower alkyloxy,aryloxy, arylthio, 5- or 6-membered heterocyclooxy, lower aralkylthio,lower aralkyloxy, lower alkylthio, lower alkynyloxy, lower alkynylthio,lower alkynyloxyalkyl, lower alkenyloxy, lower alkenylthio, loweralkenyloxyalkyl, lower alkyloxyalkyl, lower alkylthioalkyl, lowerhydroxyalkyloxy, lower alkylarylalkynyloxy, lower alkoxycarbonylalkyl,lower hydroxyalkyloxyalkyl, lower oximinoalkoxy , loweroximinoalkoxyalkyl, lower (alkyl)oximinoalkoxy, lower(alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, lowercarbonylalkyloxyalkyl,

wherein Ar is selected from phenyl, thienyl, oxazolyl, furyl, pyrrolyl,thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, and pyridyl,wherein Ar is optionally substituted with one or two substituentsselected from halo, hydroxyl, mercapto, lower alkyl, lower alkoxy, and

wherein R¹ is at least one substituent selected from thienyl, oxazolyl,furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl,pyrazolyl, cyclopentenyl, pyridyl, and phenyl, where R¹ is optionallysubstituted at a substitutable position with one or more radicalsselected from lower alkyl, lower haloalkyl, hydroxyl, lowerhydroxyalkyl, lower haloalkoxy, nitro, lower alkoxyalkyl, halo, loweralkoxy and lower alkylthio; wherein R² is selected from lower alkyl andamino; wherein R³ and R⁴ together form a tetrahydropyran ring, and whichring may bear one, two or three substituents, which may be the same ordifferent, selected from hydroxyl, lower alkyl, and lower alkoxy;wherein R⁵ is selected from hydroxyl and lower alkoxy; wherein R⁶ isselected from hydrido, and lower alkyl; and wherein R⁷ is selected fromlower alkyl and lower alkoxy; or a pharmaceutically-acceptable saltthereof.
 5. Compound of claim 4 wherein A is a radical selected fromthienyl, oxazolyl, furyl, pyrrolyl, triazolyl, thiazolyl, imidazolyl,isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl, wherein A isoptionally substituted with a radical selected from acyl, fluoro,chloro, bromo, methyl, trifluoromethyl, oxo, cyano, carboxyl, methoxy,aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl, carboxypropyl,and hydroxymethyl; wherein Y is a radical selected from oxy, ethyl,propyl, isopropyl, butyl, 1-propynyl, 2-propynyl, methhyloxy, ethyloxy,propyloxy, methylthio, (Z)-1-propenyloxy, (E)-2-propenyloxy,(Z)-2-propenyloxy, (E)-1-propenyloxy, (Z)-1-propenyloxymethyl,(E)-2-propenyloxymethyl, (Z)-2-propenyloxymethyl,(E)-1-propenyloxymethyl, 1-propynyloxy, 2-propynyloxy, 1-propynylthio,2-propynylthio, hydroxymethyloxy, 1-hydroxyethyloxy, 2-hydroxypropyloxy,hydroxymethyloxymethyl, 1-hydroxyethyloxymethyl,2-hydroxypropyloxymethyl, methyloxymethyl, ethyloxymethyl,propyloxymethyl, 1-propynyloxymethyl, oximinomethyloxy,oximinomethyloxymethyl, (methyl)oximinomethyloxy,(methyl)oximinomethyloxymethyl, triazolylmethyloxy,triazolylmethyloxymethyl, 1-(methoxycarbonyl)ethyl, methylthiomethyl,ethylthiomethyl, methylphenylpropynyloxy,N-ethyl-N-methylaminocarbonylmethyloxy, N-ethyl-N-methylaminoethyloxy,carbonylmethyloxy, carbonylbutyloxy, and carbonylmethyloxymethyl;wherein Ar is selected from thienyl, pyridyl, thiazolyl, and phenyl,where Ar is optionally substituted with one or two substituents selectedfrom fluoro, chloro, bromo, hydroxyl, mercapto, methyl, methoxy, and

wherein R¹ is selected from thienyl, oxazolyl, furyl, pyrrolyl,thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, and phenyl, whereR¹ is optionally substituted at a substitutable position with one ormore radicals selected from methyl, trifluoromethyl, hydroxyl,hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chloro,bromo, methoxy and methylthio; wherein R² is methyl or amino; wherein R³and R⁴ together form a tetrahydropyran ring, and which ring may bearone, two or three substituents, which may be the same or different,selected from hydroxyl, methyl, and methoxy; and wherein R⁵ is selectedfrom hydroxyl and methoxy; or a pharmaceutically-acceptable saltthereof.
 6. Compound of claim 5 selected from compounds and theirpharmaceutically-acceptable salts, of the group consisting of4-[2-[[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;methyl5-[4-(aminosulfonyl)phenyl]-α-[[3-(tetrahydro-4-methoxypyran-4-yl)phenyl]methyl]-4-phenyloxazole-2-acetate;N-[2-[5-[4-(aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamide;N-[2-[4-[4-(aminosulfonyl)phenyl]-5-phenyloxazol-2-yl]ethyl]-2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy-N-methylacetamide;4-[2-[[2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]ethyl]-N-methylaminoethyl]-4-phenyloxazol-5-yl]benzenesulfonamide;4-[2-[[2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]ethyl]-N-methylaminoethyl]-5-phenyloxazol-4-yl]benzenesulfonamide;4-[2-[[4-[3-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]-1-propynyl]phenyl]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;4-[2-[[4-[3-[3-fluoro-5-(tetrahydro-4-hydroxypyran-4-yl)phenoxy]-1-propynyl]-phenyl]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;4-[2-[[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-4-(4-fluorophenyl)oxazol-5-yl]benzenesulfonamide;4-[2-[4-[[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy)methyl]phenylmethyl]-4-phenyloxazol-5-yl]benzenesulfonamide;4-[5-[[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]methyl]-3-phenylisoxazol-4-yl]benzenesulfonamide;4-[2-[[[3-(tetrahydro-4-methoxypyran-4-yl)phenylmethyl]oxy]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;4-[2-[[[3-(tetrahydro-4-methoxypyran-4-yl)phenylmethyl]thio]methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;4-[2-[[[3-(tetrahydro-4-methoxypyran-4-yl)phenylmethyl]thio]ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide;4-[2-[3-(tetrahydro-4-methoxypyran-4-yl)phenyl]methoxyl-4-phenyloxazol-5-yl]benzenesulfonamide;4-[2-[3-(tetrahydro-4-methoxypyran-4-yl)phenyl]methylthio]-4-phenyloxazol-5-yl]benzenesulfonamide;N-[2-[5-[4-(aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]ethylamino]-2-[3-fluoro-5-(tetrahydro-4-methoxypyran-4-yl)phenoxy]acetamide;4-[5-(4-chlorophenyl)-3-(3-methoxyphenyl)oxymethyl-1Hpyrazol-1-yl]benzenesulfonamide;4-[5-(4-chlorophehyl)-3-(3-methoxyphenyl)thiomethyl-1Hpyrazol-1-yl]benzenesulfonamide;4-[5-(4-chlorophenyl)-3-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]-1H-pyrazol-1-yl]benzenesulfonamide;4-[5-(4-chlorophenyl)-3-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide;4-[2-[3-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide;4-[2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide;4-(4-fluorophenyl)-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]-5-(4-(methylsulfonyl)phenyl)oxazole;and4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]oxazole.7. A compound of Formula II

wherein A is a ring substituent selected from thienyl, oxazolyl, furyl,pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, triazolyl, isoxazolyl,pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A is optionallysubstituted with a radical selected from acyl, halo, hydroxyl, loweralkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy,aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lowercyanoalkyl, and lower hydroxyalkyl; wherein Y is a radical selected fromoxy, thio, sulfinyl, sulfonyl, lower alkyl, lower alkynyl, loweralkenyl, lower hydroxyalkyl, aryl, lower cycloalkyl, 5- or 6-memberedheterocyclo, aralkyl, lower alkyloxy, aryloxy, arylthio, lowercycloalkyloxy, 5- or 6-membered heterocyclooxy, lower aralkylthio, loweraralkyloxy, lower alkylthio, lower alkynyloxy, lower alkynylthio, loweralkynyloxyalkyl, lower alkenyloxy, lower alkenylthio, loweralkenyloxyalkyl, lower alkyloxyalkyl, lower alkylthioalkyl, lowerhydroxyalkylthio, lower hydroxyalkylthioalkyl, lower oximinoalkylthio,lower oximinoalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower(alkyl)oximinoalkylthioalkyl, lower alkylarylalkynyloxy, lowerdialkylaminoalkyloxy, lower dialkylaminocarbonylalkyloxy, loweralkoxycarbonylalkyl, lower carbonylalkylthio, lowercarbonylalkylthioalkyl, lower hydroxyalkyloxy, lowerhydroxyalkyloxyalkyl, lower oximinoalkoxy, lower oximinoalkoxyalkyl,lower (alkyl)oximinoalkoxy, lower (alkyl)oximinoalkoxyalkyl, lowercarbonylalkyloxy, and lower carbonylalkyloxyalkyl; wherein R¹ is asubstituent selected from 5- and 6-membered heterocyclo, lowercycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyland naphthyl, wherein R¹ is optionally substituted at a substitutableposition with one or more radicals selected from lower alkyl, lowerhaloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lowerhydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino,lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and loweralkylthio; wherein R² is selected from lower alkyl and amino; wherein R⁹is one or two substituents selected from halo, hydroxyl, amino, nitro,cyano, carbamoyl, alkyl, alkenyloxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylamino, dialkylamino, haloalkyl, alkoxycarbonyl,N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkanoylamino, cyanoalkoxy,carbamoylalkoxy, and alkoxycarbonylalkoxy; and wherein R¹⁰ is selectedfrom hydrido, alkyl, alkenyl, alkynyl, cyanoalkyl, alkanoyl, and benzoyloptionally substituted with a substituent selected from halo, alkyl andalkoxy; or a pharmaceutically-acceptable salt thereof.
 8. Compound ofclaim 7 wherein A is a ring substituent selected from thienyl, oxazolyl,furyl, pyrrolyl, thiazolyl, imidazolyl, triazolyl, isoxazolyl,pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A is optionallysubstituted with a radical selected from acyl, halo, hydroxyl, loweralkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy,aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lowercyanoalkyl, and lower hydroxyalkyl; wherein Y is a radical selected fromoxy, lower alkyl, lower alkynyl, 5- or 6-membered heterocyclo, lowerheterocyloalkyloxyalkyl, lower hydroxyalkyl, lower alkyloxy, loweralkylthio, lower alkyloxyalkyl, lower alkenyloxy, lower alkenyloxyalkyl,lower alkynyloxy, lower alkynylthio, lower alkynyloxyalkyl, loweralkylthioalkyl, lower hydroxyalkylthio, lower hydroxyalkylthioalkyl,lower oximinoalkylthio, lower oximinoalkylthioalkyl, lower(alkyl)oximinoalkylthio, lower (alkyl)oximinoalkylthioalkyl, lowercarbonylalkylthio, lower carbonylalkylthioalkyl, loweralkylarylalkynyloxy, lower dialkylaminoalkyloxy, lowerdialkylaminocarbonylalkyloxy, lower alkoxycarbonylalkyl, lowerhydroxyalkyloxy, lower hydroxyalkyloxyalkyl, lower oximinoalkoxy, loweroximinoalkoxyalkyl, lower (alkyl)oximinoalkoxy, lower(alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxy, and lowercarbonylalkyloxyalkyl; wherein R¹ is phenyl optionally substituted at asubstitutable position with one or more radicals selected from loweralkyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, halo, and loweralkoxy; wherein R² is selected from lower alkyl and amino; wherein R⁹ isone or two substituents selected from halo, hydroxyl, amino, loweralkyl, lower alkoxy; and wherein R¹⁰ is selected from hydrido, and loweralkyl; or a pharmaceutically-acceptable salt thereof.
 9. Compound ofclaim 8 wherein A is a radical selected from thienyl, oxazolyl, furyl,pyrrolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, cyclopentenyl,phenyl, and pyridyl; wherein A is optionally substituted with a radicalselected from formyl, fluoro, chloro, bromo, hydroxyl, methyl, ethyl,isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, oxo,cyano, nitro, carboxyl, methoxy, ethoxy, propoxy, n-butoxy, pentoxy,hexyloxy, methylenedioxy, aminocarbonyl, methoxycarbonyl, carboxypropyl,carboxymethyl, carboxyethyl, cyanomethyl, and hydroxymethyl; wherein Yis a radical selected from oxy, ethyl, propyl, isopropyl, butyl,1-propynyl, 2-propynyl, methyloxy, ethyloxy, propyloxy, methylthio,(Z)-1-propenyloxy, (E)-2-propenyloxy, (Z)-2-propenyloxy,(E)-1-propenyloxy, (Z)-1-propenyloxymethyl, (E)-2-propenyloxymethyl,(Z)-2-propenyloxymethyl, (E)-1-propenyloxymethyl, 1-propynyloxy,2-propynyloxy, 1-propynylthio, 2-propynylthio, hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxymethyloxy, 1-hydroxyethyloxy,2-hydroxypropyloxy, hydroxymethyloxymethyl, 1-hydroxyethyloxymethyl,2-hydroxypropyloxymethyl, methyloxymethyl, ethyloxymethyl,propyloxymethyl, 1-propynyloxymethyl, hydroxymethylthio,1-hydroxyethylthio, 2-hydroxypropylthio, hydroxymethylthiomethyl,1-hydroxyethylthiomethyl, 2-hydroxypropylthiomethyl, oximinomethylthio,oximinomethylthiomethyl, (methyl)oximinomethylthio,(methyl)oximinomethylthiomethyl, triazolylmethyloxy,triazolylmethyloxymethyl, carbonylmethylthio, carbonylbutylthio,carbonylmethylthiomethyl, oximinomethyloxy, oximinomethyloxymethyl,(methyl)oximinomethyloxy, methylthiomethyl,(methyl)oximinomethyloxymethyl, ethylthiomethyl,1-(methoxycarbonyl)ethyl, methylphenylpropynyloxy,N-ethyl-N-methylaminocarbonylmethyloxy, N-ethyl-N-methylaminoethyloxy,triazolyl, carbonylmethyloxy, carbonylbutyloxy, andcarbonylmethyloxymethyl; wherein R¹ is phenyl optionally substituted ata substitutable position with one or more radicals selected from methyl,ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, fluoro,dichloropropyl, hydroxyl, hydroxymethyl, chloro, bromo, methoxy, ethoxy,propoxy, n-butoxy, pentoxy, and hexyloxy; wherein R² is selected frommethyl and amino; wherein R⁹ is one or two substituents selected fromfluoro, chloro, bromo, hydroxyl, amino, methyl, ethyl, isopropyl, butyl,tert-butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, propoxy, n-butoxy,pentoxy, and hexyloxy; and wherein R¹⁰ is selected from hydrido, andmethyl; or a pharmaceutically-acceptable salt thereof.
 10. Apharmaceutical composition comprising a therapeutically-effective amountof a compound of claim 1-9, or a pharmaceutically-acceptable saltthereof.
 11. A method of treating a condition benefited by theinhibition of 5-lipoxygenase, cyclooxygenase-2 or both 5-lipoxygenaseand cyclooxygenase-2, said method comprising treating the subject havingor susceptible to such inflammation or inflammation-associated disorder,with a therapeutically-effective amount of a compound of claim 1-9, or apharmaceutically-acceptable salt thereof.
 12. The method of claim 11wherein the condition is inflammation or an inflammation-associateddisorder.
 13. The method of claim 12 wherein the condition isinflammation.
 14. The method of claim 12 wherein the condition is aninflammation-associated disorder.
 15. The method of claim 14 wherein theinflammation-associated disorder is arthritis.
 16. The method of claim14 wherein the inflammation-associated disorder is pain.
 17. The methodof claim 14 wherein the inflammation-associated disorder is fever.